Alternative titles; symbols
HGNC Approved Gene Symbol: KDR
Cytogenetic location: 4q12 Genomic coordinates (GRCh38): 4:55,078,481-55,125,595 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4q12 | {Hemangioma, capillary infantile, susceptibility to} | 602089 | Autosomal dominant | 3 |
| Hemangioma, capillary infantile, somatic | 602089 | 3 |
The gene for KDR (kinase insert domain receptor), a growth factor receptor tyrosine kinase, was cloned from a human endothelial cell cDNA library (Terman et al., 1991). The predicted amino acid sequence contained multiple characteristics (e.g., an ATP binding site, a membrane spanning region, split tyrosine kinase regions) typical of known type III receptor tyrosine kinases (e.g., platelet-derived growth factor receptor (173410), colony stimulating factor-1 receptor (164770), fibroblast growth factor receptor (176943), and KIT (164920)).
By RT-PCR analysis of human umbilical vein endothelial cells, Albuquerque et al. (2009) cloned a secreted splice variant of VEGFR2 (sVEGFR2), resulting from retention of intron 13 containing an in-frame termination codon. The truncated protein contains 679 amino acids with a unique 16-amino acid C-terminal sequence. The authors also cloned mouse sVegfr2, which encodes a polypeptide of 673 amino acids with a unique 13-amino acid C-terminal sequence. In situ hybridization and immunolocalization showed sVegfr2 in mouse corneal epithelium and stroma, with similar localization of sVEGRF2 in human cornea.
Terman et al. (1991) localized the KDR gene to chromosome 4 by Southern analysis of a panel of human-mouse somatic cell hybrid DNAs. By fluorescence in situ hybridization, Terman et al. (1992) mapped the KDR gene to chromosome 4q31.2-q32. Spritz et al. (1994) studied a YAC contig spanning 3 type III receptor protein tyrosine kinase genes--PDGFRA (173490), KIT (164920), and KDR--located in chromosome 4q12. Sait et al. (1995) likewise corrected the assignment to chromosome 4q11-q12 to the same region occupied also by PDGFRA and KIT, thus indicating the location of a cluster of receptor tyrosine kinase genes.
Vascular endothelial growth factor (VEGF; 192240) is the only mitogen that specifically acts on endothelial cells. Its expression is upregulated by hypoxia, and its cell-surface receptor, known as fetal liver kinase-1 (Flk1) in mouse, is exclusively expressed in endothelial cells (Millauer et al., 1993; Plate et al., 1993). Flk1 is the mouse homolog of KDR (Matthews et al., 1991). KDR and its mouse homolog bind vascular endothelial growth factor with high affinity in vitro and are expressed early in development by endothelial cell precursors (Quinn et al., 1993). The mouse homolog has been implicated in the development of blood and blood vessels. For this reason and because KDR maps to the same region of chromosome 4 as the gene for familial total anomalous pulmonary venous return (TAPVR1; 106700), Bleyl et al. (1995) considered KDR to be a strong candidate for the site of mutation in that disorder.
To investigate the biologic relevance of the Flk1/VEGF receptor/ligand system for angiogenesis, Millauer et al. (1994) used a replication-defective recombinant MSV retrovirus encoding a dominant-negative mutant of mouse Flk1 to infect endothelial target cells in vivo. They found that, if cells producing significant titers of dominant-negative mutant-carrying virus were co-implanted in nude mice along with an aggressive tumor-forming rat cell line, the tumor growth was prevented. The results emphasized the central role of the Flk1/VEGF system in angiogenesis in general and in the development of solid tumors in particular.
Kendall et al. (1996) showed that a soluble form of FLT1 (165070) forms heterodimers with the extracellular domain of FLK1.
Studies on pluripotent hematopoietic stem cells had been hindered by lack of a positive marker comparable to the CD34 marker of hematopoietic progenitor cells. Ziegler et al. (1999) found that in human postnatal hematopoietic tissues, 0.1 to 0.5% of CD34+ cells expressed vascular endothelial growth factor receptor-2, or KDR. Ziegler et al. (1999) demonstrated that pluripotent hematopoietic stem cells were restricted to the CD34+KDR+ cell fraction. Conversely, lineage-committed hematopoietic progenitor cells were in the CD34+KDR- subset. On the basis of limiting dilution analysis, the hematopoietic stem cell frequency in the CD34+KDR+ fraction was 20% in bone marrow by mouse xenograft assay and 25 to 42% in bone marrow, peripheral blood, and cord blood by the 12-week long-term culture assay. The latter values rose to 53 to 63% in the long-term culture supplemented with VEGF and to greater than 95% for the cell subfraction resistant to growth factor starvation. Ziegler et al. (1999) concluded that KDR is a positive functional marker defining stem cells and distinguishing them from progenitors.
Interaction between endothelial cells and mural cells (pericytes and vascular smooth muscle) is essential for vascular development and maintenance. Endothelial cells arise from Flk1-expressing (Flk1+) mesoderm cells, whereas mural cell are believed to derive from mesoderm, neural crest, or epicardial cells and migrate to form the vessel wall. Yamashita et al. (2000) showed that Flk1+ cells derived from embryonic stem cells can differentiate into both endothelial and mural cells and can reproduce the vascular organization process. VEGF promotes endothelial cell differentiation, whereas mural cells are induced by platelet-derived growth factor-BB (PDGFB; 190040). Vascular cells derived from Flk1+ cells can organize into vessel-like structures consisting of endothelial tubes supported by mural cells in 3-dimensional culture. Injection of Flk1+ cells into chick embryos showed that they can incorporate as endothelial and mural cells and contribute to the developing vasculature in vivo. Yamashita et al. (2000) concluded that Flk1+ cells can act as vascular progenitor cells to form mature vessels.
Basu et al. (2001) reported that at nontoxic levels, the neurotransmitter dopamine strongly and selectively inhibited the vascular permeabilizing and angiogenic activities of VEGF. Dopamine acted through D2 dopamine receptors (126450) to induce endocytosis of VEGF receptor 2, which is critical for promoting angiogenesis, thereby preventing VEGF binding, receptor phosphorylation, and subsequent signaling steps. The action of dopamine was specific for VEGF and did not affect other mediators of microvascular permeability or endothelial-cell proliferation or migration. Basu et al. (2001) concluded that their results reveal a link between the nervous system and angiogenesis and indicate that dopamine and other D2 receptors might have value in anti-angiogenesis therapy.
Most severe visual loss results from complications associated with retinal neovascularization in patients with ischemic ocular diseases such as diabetic retinopathy, retinal vein occlusion, and retinopathy of prematurity (ROP). Intraocular expression of VEGF is closely correlated with neovascularization in these human disorders and with ischemia-induced retinal neovascularization in mice. Aiello et al. (1995) reported that VEGF-neutralizing chimeric proteins, constructed by joining the extracellular domain of high-affinity VEGF receptors with the heavy chain of IgG, substantially reduced the development of retinal neovascularization when injected into the eyes of mice with ischemic retinal disease. The inhibition was specific to VEGF-receptor chimeric proteins, was dose-dependent, and occurred in the absence of any histologically evident ocular toxicity or inflammation. The study suggested that VEGF serves a causal role in some forms of retinal angiogenesis and proved the potential of VEGF inhibition as therapy for certain ischemic retinal diseases, thereby circumventing the inherent retinal destruction produced by laser photocoagulation and cryotherapy.
Fulton et al. (2001) studied the electroretinographic (ERG) responses in 25 children characterized by maximum, acute phase ROP (none, mild, moderate, severe, and very severe). In the none to severe categories, the ERG responses varied significantly with the severity of acute phase ROP. In the very severe category, the ERG responses were too attenuated to calculate the responses. The authors concluded that rod photoreceptors must be involved in ROP. They found that the more severe the acute phase ROP, the more severe the compromise of the processes involved in the activation of phototransduction in the rods.
Capillary hemangiomas (602089) are the most common tumors of infancy, occurring in as many as 10% of all births. These benign vascular lesions enlarge rapidly during the first year of life by hyperplasia of endothelial cells and attendant pericytes and then spontaneously involute over a period of years, leaving loose fibrofatty tissue. The possibility has been raised that the tumor is a result of somatic mutation in 1 or more components of critical vascular growth-regulatory pathways. To test this hypothesis, Walter et al. (2002) obtained 15 proliferative-phase hemangiomas from surgical resection and dissected them to enrich for the lesional (endothelial and pericytic) components of each specimen. To determine whether hemangiomas represent a clonal expansion from a single progenitor cell, they assayed X-inactivation patterns for each lesion by using the polymorphic X-linked human androgen receptor gene (AR; 313700). Twelve of 14 informative hemangiomas showed a significant degree of allelic loss, suggesting a nonrandom X-inactivation pattern, and thus a monoclonal origin. Sequencing of the VEGFRs as candidates for the site of somatic mutations revealed mutations in 2 of the 15 hemangioma specimens: a missense mutation (P1147S; 191306.0001) in the kinase domain of VEGFR2 in one specimen and a missense mutation (P954S; 136352.0007) in the kinase insert of the VEGFR3 gene in another. These results suggested that 1 potential mechanism involved in hemangioma formation is the alteration of the VEGF signaling pathway in endothelial and/or pericytic cells.
TIMP3 (188826) encodes a potent angiogenesis inhibitor and is mutated in Sorsby fundus dystrophy (136900), a macular degenerative disease with submacular choroidal neovascularization. Qi et al. (2003) demonstrated the ability of TIMP3 to inhibit VEGF-mediated angiogenesis and identified the potential mechanism by which this occurs: TIMP3 blocks the binding of VEGF to VEGFR2 and inhibits downstream signaling and angiogenesis. This property seems to be independent of its MMP-inhibitory activity, indicating a new function for TIMP3.
Autiero et al. (2003) reported that placental growth factor (PGF; 601121) regulates inter- and intramolecular crosstalk between the VEGF receptor tyrosine kinases FLT1 (165070) and FLK1. Activation of FLT1 by PGF resulted in intermolecular transphosphorylation of FLK1, thereby amplifying VEGF-driven angiogenesis through FLK1. Even though VEGF and PGF both bind FLT1, PGF uniquely stimulated the phosphorylation of specific FLT1 tyrosine residues and the expression of distinct downstream target genes. Furthermore, the VEGF/PGF heterodimer activated intramolecular VEGF receptor crosstalk through formation of FLK1/FLT1 heterodimers. Autiero et al. (2003) concluded that the inter- and intramolecular VEGF receptor crosstalk is likely to have therapeutic implications, as treatment with VEGF/PGF heterodimer or a combination of VEGF plus PGF increased ischemic myocardial angiogenesis in a mouse model that was refractory to VEGF alone.
VEGF is a key growth factor during vascular development and one of its receptors, KDR, plays a pivotal role in endothelial cell proliferation and differentiation. Gogat et al. (2004) analyzed VEGF and KDR gene expression in the ocular structures of 7-week-old embryos and 10- and 18-week-old fetuses. Their results demonstrated that the levels of VEGF and KDR transcripts were correlated during the normal development of the ocular vasculature in humans. The complementarity between the patterns of VEGF and KDR during the early stages of development suggested that VEGF-KDR interactions played a major role in the formation and regression of the hyaloid vascular system and in the development of the choriocapillaris. In later stages (i.e., 18-week-old fetuses), the expression of KDR seemed to be linked to the development of the retinal vascular system. VEGF and KDR transcripts were unexpectedly detected in some nonvascular tissues, i.e., in the cornea and in the retina before the development of the retinal vascular system. Gogat et al. (2004) concluded that VEGF might also be necessary for nonvascular retinal developmental functions, especially for the coordination of neural retinal development and the preliminary steps of the establishment of the definitive stable retinal vasculature.
Tzima et al. (2005) investigated the pathway upstream of integrin (see 192975) activation leading to fluid shear stress response in vascular endothelial cells. They found that PECAM1 (173445), which directly transmits mechanical force, vascular endothelial cell cadherin (601120), which functions as an adaptor, and VEGFR2, which activates phosphatidylinositol-3-OH kinase, comprise a mechanosensory complex. Together, these receptors were sufficient to confer responsiveness to flow in heterologous cells. In support of the relevance of this pathway in vivo, Pecam1 knockout mice did not activate NF-kappa-B (see 164011) and downstream inflammatory genes in regions of disturbed flow. Therefore, Tzima et al. (2005) concluded that this mechanosensing pathway is required for the earliest known events in atherogenesis.
Jin et al. (2006) found that hematopoietic cytokines, particularly Kitlg (184745) and Tpo (THPO; 600044), induced release of Sdf1 (600835) from mouse platelets and enhanced neovascularization of ischemic hindlimbs through mobilization of Cxcr4 (162643)-positive/Vegfr1-positive hematopoietic progenitors termed hemangiocytes. Revascularization was profoundly impaired in Mmp9 (120361)-deficient mice, which have impaired release of soluble Kitlg from membrane Kitlg, as well as Tpo-deficient mice and Tpor (MPL; 159530)-deficient mice. Transplantation of Cxcr4-positive/Vegfr1-positive hemangiocytes restored revascularization in Mmp9-deficient mice. Jin et al. (2006) concluded that hematopoietic cytokines, through graded deployment of platelet-derived SDF1, support mobilization and recruitment of CXCR4-positive/VEGFR-positive hemangiocytes.
To determine whether a progenitor is present during human cardiogenesis, Yang et al. (2008) analyzed the development of the cardiovascular lineages in human embryonic stem cell differentiation cultures. They showed that after induction with combinations of activin A (see 147390), BMP4 (112262), FGF2 (134920), VEGF (192240), and DKK1 (605189) in serum-free media, human embryonic stem cell-derived embryoid bodies generated a KDR(low)/C-KIT (CD117; 164920)-negative population that displayed cardiac, endothelial, and vascular smooth muscle potential in vitro and, after transplantation, in vivo. When plated in monolayer cultures, these KDR(low)/C-KIT(negative) cells differentiated to generate populations consisting of greater than 50% contracting cardiomyocytes. Populations derived from the KDR(low)/C-KIT(negative) fraction gave rise to colonies that contain all 3 lineages when plated in methylcellulose cultures. Results from limiting dilution studies and cell-mixing experiments supported the interpretation that these colonies are clones, indicating that they had developed from a cardiovascular colony-forming cell. Yang et al. (2008) concluded that their findings identified a human cardiovascular progenitor that defines one of the earliest stages of human cardiac development.
Greenberg et al. (2008) defined a role for VEGF as an inhibitor of neovascularization on the basis of its capacity to disrupt vascular smooth muscle cell function. Specifically, under conditions of platelet-derived growth factor (PDGF; see 173430)-mediated angiogenesis, VEGF ablates pericyte coverage of nascent vascular sprouts, leading to vessel destabilization. At the molecular level, VEGF-mediated activation of VEGFR2 suppresses PDGFRB (173410) signaling in vascular smooth muscle cells through the assembly of a receptor complex consisting of PDGFRB and VEGFR2. Inhibition of VEGFR2 not only prevents assembly of this receptor complex but also restores angiogenesis in tissues exposed to both VEGF and PDGF. Finally, genetic deletion of tumor cell VEGF disrupts PDGFRB/VEGFR2 complex formation and increases tumor vessel maturation. Greenberg et al. (2008) concluded that their findings underscored the importance of vascular smooth muscle cells/pericytes in neovascularization and revealed a dichotomous role for VEGF and VEGFR2 signaling as both a promoter of endothelial cell function and a negative regulator of vascular smooth muscle cells and vessel maturation.
Stockmann et al. (2008) showed that the deletion of inflammatory cell-derived VEGFA attenuates the formation of a typical high density vessel network, thus blocking the angiogenic switch in solid tumors in mice. Vasculature in tumors lacking myeloid cell-derived VEGFA was less tortuous, with increased pericyte coverage and decreased vessel length, indicating vascular normalization. In addition, loss of myeloid-derived VEGFA decreased the phosphorylation of VEGFR2 in tumors, even though overall VEGFA levels in the tumors were unaffected. However, deletion of myeloid cell VEGFA resulted in an accelerated tumor progression in multiple subcutaneous isograft models and an autochthonous transgenic model of mammary tumorigenesis, with less overall tumor cell death and decreased tumor hypoxia. Furthermore, loss of myeloid cell VEGFA increased the susceptibility of tumors to chemotherapeutic cytotoxicity. Stockmann et al. (2008) concluded that myeloid-derived VEGFA is essential for the tumorigenic alteration of vasculature and signaling to VEGFR2, and that these changes act to retard, not promote, tumor progression.
Mammoto et al. (2009) showed that the Rho inhibitor p190RhoGAP (GRLF1; 605277) controls capillary network formation in vitro in human microvascular endothelial cells and retinal angiogenesis in vivo by modulating the balance of activities between 2 antagonistic transcription factors, TFII-I (GTF21; 601679) and GATA2 (137295), that govern gene expression of VEGFR2. Moreover, this angiogenesis signaling pathway is sensitive to extracellular matrix elasticity as well as soluble VEGF. Mammoto et al. (2009) suggested that this finding represented the first known functional crossantagonism between transcription factors that controls tissue morphogenesis, and that responds to both mechanical and chemical cues.
Albuquerque et al. (2009) showed that secreted VEGFR2 (sVEGFR2) inhibits developmental and reparative lymphangiogenesis by blocking VEGFC (601528) function. Tissue-specific loss of sVegfr2 in mice induced spontaneous lymphatic invasion of the cornea and hyperplasia of skin lymphatics without affecting blood vasculature. Administration of sVegfr2 inhibited lymphangiogenesis but not hemangiogenesis induced by corneal suture injury or transplantation and enhanced corneal allograft survival in mice; in addition, human sVEGFR2 suppressed the proliferation of human lymphangioma endothelial cells. Albuquerque et al. (2009) concluded that naturally occurring sVEGFR2 acts as a molecular uncoupler of blood and lymphatic vessels.
Using flow cytometric, RT-PCR, and Western blot analysis, Basu et al. (2010) determined that CD45RO (PTPRC; 151460)-positive CD4-positive memory T lymphocytes expressed KDR and FLT1 and that VEGF increased the phosphorylation and activation of ERK (see 601795) and AKT (164730) in these cells. VEGF-mediated signaling was inhibited by specific siRNA or pharmacologic inhibitor. VEGF also augmented mitogen-induced production of IFNG (147570) and memory T cell chemotaxis. Basu et al. (2010) concluded that VEGF and KDR have important roles in CD45RO-positive memory T cell responses.
Sawamiphak et al. (2010) showed that ephrin-B2 (EFNB2; 600527) reverse signaling involving PDZ interactions regulates endothelial tip cell guidance to control angiogenic sprouting and branching in physiologic and pathologic angiogenesis. In vivo, ephrin-B2 PDZ signaling-deficient mice exhibited a reduced number of tip cells with fewer filopodial extensions at the vascular front in the mouse retina. In pathologic settings, impaired PDZ signaling decreased tumor vascularization and growth. Mechanistically, Sawamiphak et al. (2010) showed that ephrin-B2 controls VEGF receptor (VEGFR2) internalization and signaling. Importantly, internalization of VEGFR2 is necessary for activation and downstream signaling of the receptor and is required for VEGF-induced tip cell filopodial extension. Sawamiphak et al. (2010) concluded that ephrin-B2 at the tip cell filopodia regulates the proper spatial activation of VEGFR2 endocytosis and signaling to direct filopodial extension.
Ding et al. (2010) demonstrated that liver sinusoidal endothelial cells (LSECs) constitute a unique population of phenotypically and functionally defined Vegfr3 (136352)+/Cd34 (142230)-/Vegfr2+/VE-cadherin (601120)+/factorVIII (300841)+/Cd45 (151460)- endothelial cells, which through the release of angiocrine trophogens initiate and sustain liver regeneration induced by 70% partial hepatectomy. After partial hepatectomy, residual liver vasculature remains intact without experiencing hypoxia or structural damage, which allows study of physiologic liver regeneration. Using this model, Ding et al. (2010) showed that inducible genetic ablation of Vegfr2 in the LSECs impairs the initial burst of hepatocyte proliferation (days 1-3 after partial hepatectomy) and subsequent reconstitution of the hepatovascular mass (days 4-8 after partial hepatectomy) by inhibiting upregulation of the endothelial cell-specific transcription factor Id1 (600349). Accordingly, Id1-deficient mice also manifested defects throughout liver regeneration, owing to diminished expression of LSEC-derived angiocrine factors, including hepatocyte growth factor (HGF; 142409) and Wnt2 (147870). Notably, in in vitro cocultures, Vegfr2-Id1 activation in LSECs stimulated hepatocyte proliferation. Indeed, intrasplenic transplantation of Id1 wildtype or Id1-null LSECs transduced with Wnt2 and Hgf reestablished an inductive vascular niche in the liver sinusoids of the Id1-null mice, initiating and restoring hepatovascular regeneration. Therefore, Ding et al. (2010) concluded that in the early phases of physiologic liver regeneration, VEGFR2-ID1-mediated inductive angiogenesis in LSECs through release of angiocrine factors WNT2 and HGF provokes hepatic proliferation. Subsequently, VEGFR2-ID1-dependent proliferative angiogenesis reconstitutes liver mass.
Beck et al. (2011) used a mouse model of skin tumors to investigate the impact of the vascular niche and VEGF signaling on controlling the stemness of squamous skin tumors during the early stages of tumor progression. They showed that cancer stem cells of skin papillomas are localized in a perivascular niche, in the immediate vicinity of endothelial cells. Furthermore, blocking Vegfr2 caused tumor regression not only by decreasing the microvascular density, but also by reducing cancer stem cell pool size and impairing cancer stem cell renewal properties. Conditional deletion of Vegfa (192240) in tumor epithelial cells caused tumors to regress, whereas Vegf overexpression by tumor epithelial cells accelerated tumor growth. In addition to its well-known effect on angiogenesis, Vegf affected skin tumor growth by promoting cancer stemness and symmetric cancer stem cell division, leading to cancer stem cell expansion. Moreover, deletion of neuropilin-1 (Nrp1; 602069), a VEGF coreceptor expressed in cutaneous cancer stem cells, blocked Vegf's ability to promote cancer stemness and renewal. Beck et al. (2011) concluded that their results identified a dual role for tumor cell-derived VEGF in promoting cancer stemness: by stimulating angiogenesis in a paracrine manner, VEGF creates a perivascular niche for cancer stem cells, and by directly affecting cancer stem cells through NRP1 in an autocrine loop, VEGF stimulates cancer stemness and renewal. Finally, deletion of NRP1 in normal epidermis prevents skin tumor initiation.
Benedito et al. (2012) used inducible loss-of-function genetics in combination with inhibitors in vivo to demonstrate that DLL4 (605185) protein expression in retinal tip cells is only weakly modulated by VEGFR2 signaling. Surprisingly, Notch (190198) inhibition also had no significant impact on VEGFR2 expression and induced deregulated endothelial sprouting and proliferation even in the absence of VEGFR2, which is the most important VEGFA receptor and is considered to be indispensable for these processes. By contrast, VEGFR3, the main receptor for VEGFC (601528), was strongly modulated by Notch. VEGFR3 kinase activity inhibitors but not ligand-blocking antibodies suppressed the sprouting of endothelial cells that had low Notch signaling activity. Benedito et al. (2012) concluded that their results established that VEGFR2 and VEGFR3 are regulated in a highly differential manner by Notch. They proposed that successful antiangiogenic targeting of these receptors and their ligands will strongly depend on the status of endothelial Notch signaling.
By coexpression and knockdown analyses, Maghsoudlou et al. (2016) showed that ring finger protein-121 (RNF121; 620529) regulated maturation of VEGFR2 in human endothelial cells. RNF121 was involved in exit of VEGFR2 from endoplasmic reticulum to Golgi complexes and thereby restricted trafficking of VEGFR2 to the cell surface. By inhibiting VEGFR2 maturation, RNF121 attenuated VEGF-induced tyrosine phosphorylation of VEGFR2 and activation of downstream signaling proteins. RNF121 physically interacted with the cytoplasmic domain of immature VEGFR2 and ubiquitinated VEGFR2 to regulate its maturation. Mutation analysis revealed that the RING domain of RNF121 was important for ubiquitination. Knockdown and overexpression analyses in human primary endothelial cells showed that RNF121 activity inhibited VEGF-induced angiogenesis.
Zhang et al. (2018) showed that preventing lacteal chylomicron uptake by inducible endothelial genetic deletion of Nrp1 and Vegfr1 (FLT1; 165070) renders mice resistant to diet-induced obesity. Absence of Nrp1 and Flt1 receptors increased Vegfa bioavailability and signaling through Vegfr2, inducing lacteal junction zippering and chylomicron malabsorption. Restoring permeable lacteal junctions by Vegfr2 and vascular endothelial-cadherin signaling inhibition rescued chylomicron transport in mutant mice. Zippering of lacteal junctions by disassembly of cytoskeletal vascular endothelial-cadherin anchors prevented chylomicron uptake in wildtype mice.
In 2 unrelated patients with infantile capillary hemangioma (602089), Jinnin et al. (2008) identified a germline mutation in the KDR gene (C482R; 191306.0002).
Shalaby et al. (1995) generated mice deficient in Flk1 by disruption of the gene using homologous recombination in embryonic stem (ES) cells. Embryos homozygous for this mutation died in utero between 8.5 and 9.5 days postcoitum as the result of an early defect in the development of hematopoietic and endothelial cells. Yolk-sac blood islands were absent at 7.5 days, organized blood vessels could not be observed in the embryo or yolk sac at any stage, and hematopoietic progenitors were severely reduced. Fong et al. (1995) examined the role of another VEGF1 receptor, Flt1 (165070), by similarly generating mice homozygous for a targeted mutation in the gene. These mice formed blood and blood vessels, but the organization of the blood vessels was grossly perturbed, again leading to death in utero.
Matsumoto et al. (2001) found that early endothelial cells in mouse embryos surround newly specified hepatic endoderm and delimit the mesenchymal domain into which the liver bud grows. In flk1 mutant embryos, which lack endothelial cells, hepatic specification occurs, but liver morphogenesis fails prior to mesenchyme invasion. Matsumoto et al. (2001) developed an embryo tissue explant system that permits liver bud vasculogenesis and demonstrated that in the absence of endothelial cells, or when the latter are inhibited, there is a selective defect in hepatic outgrowth. Matsumoto et al. (2001) concluded that vasculogenic endothelial cells and nascent vessels are critical for the earliest stages of organogenesis, prior to blood vessel function.
Blood flow interactions with the vascular endothelium represent a specialized example of mechanical regulation of cell function that has important physiologic and pathophysiologic cardiovascular consequences. Shay-Salit et al. (2002) examined the mechanism of mechanotransduction in cultured bovine aortic endothelial cells. They showed that shear stress induced a rapid induction as well as nuclear translocation of Vegfr2 and promoted the binding of Vegfr2 and the adherens junction molecules, VE-cadherin (601120) and beta-catenin (116806), to the endothelial cytoskeleton. The changes were accompanied by the formation of a complex containing these 3 molecular entities. In endothelial cells lacking VE-cadherin, shear stress did not augment nuclear localization of the VEGF receptor-2 and phosphorylation of Akt1 (164730) and P38 (600289) as well as transcriptional induction of a reporter gene regulated by a shear stress-responsive promoter. The results suggested that VEGF receptor-2 and the adherens junction act as shear-stress cotransducers, mediating the transduction of shear-stress signals into vascular endothelial cells.
Tumor cells are elusive targets of immunotherapy due to their heterogeneity and genetic instability. The attractive alternative of inhibiting tumor growth by attacking the tumor's vascular supply was pioneered by Folkman (1998). Niethammer et al. (2002) described a novel oral DNA vaccine carried by attenuated Salmonella typhimurium that, through regulated Flk1, targeted stable, proliferating endothelial cells in the tumor vasculature rather than tumor cells. Niethammer et al. (2002) established the efficacy of gene transfer from attenuated S. typhimurium into Peyer patches by GFP expression in cells derived from Peyer patches in mice at different times after vaccine administration. The vaccine effectively protected the mice from lethal challenges with melanoma, colon carcinoma, and lung carcinoma cells and reduced growth of established metastases in a therapeutic setting. Cytolytic T lymphocyte (CTL)-mediated killing of endothelial cells indicated breaking of peripheral immune tolerance against this self antigen, resulting in markedly reduced dissemination of spontaneous and experimental pulmonary metastases. Angiogenesis in the tumor vasculature was suppressed without impairment of fertility, neuromuscular performance, or hematopoiesis, albeit with a slight delay in wound healing.
Hematopoietic and vascular cells are thought to arise from a common progenitor called the hemangioblast. Support for this concept has been provided by embryonic stem (ES) cell differentiation studies that identified the blast colony-forming cell (BL-CFC), a progenitor with both hematopoietic and vascular potential. Using conditions that support the growth of BL-CFCs, Huber et al. (2004) identified comparable progenitors that can form blast cell colonies (displaying hematopoietic and vascular potential) in gastrulating mouse embryos. Cell mixing and limiting dilution analyses provided evidence that these colonies are clonal, indicating that they develop from a progenitor with hemangioblast potential. Embryo-derived hemangioblasts were first detected at the mid-streak stage of gastrulation and peaked in number during the neural plate stage. Analysis of embryos carrying complementary DNA of the green fluorescent protein targeted to the brachyury locus demonstrated that the hemangioblast is a subpopulation of mesoderm that coexpresses brachyury (also known as T, 601397) and Flk1 (also known as Kdr). Detailed mapping studies revealed that hemangioblasts are found at highest frequency in the posterior region of the primitive streak, indicating that initial stages of hematopoietic and vascular commitment occur before blood island development in the yolk sac.
In laser-injury studies in mice, Nozaki et al. (2006) observed that injury-induced choroidal neovascularization (CNV) was increased by excess Vegf before injury but was suppressed by Vegf after injury. This effect was mediated via Vegfr1 activation and Vegfr2 deactivation: excess Vegf increased CNV before injury because Vegfr1 activation was silenced by Sparc (182120), and a transient decline in Sparc after injury created a temporal window in which Vegf signaling was routed primarily through Vegfr1.
In Kdr(fl/-) Nes-Cre mutant mice lacking Kdr in the neural lineage, Cariboni et al. (2015) observed only faint expression of Kdr in GnRH (152760) neurons at embryonic day 17.5 compared to wildtype mice. In addition, the mutant mice had a significantly reduced number of GnRH neurons compared with control littermates.
In 1 of 15 hemangioma (602089) specimens, Walter et al. (2002) found a pro1147-to-ser (P1147S) missense mutation in the kinase domain of the VEGFR2 gene.
In 2 unrelated patients with infantile hemangioma (602089), Jinnin et al. (2008) identified a germline T-to-C transition in the KDR gene, resulting in a cys482-to-arg (C482R) substitution in the extracellular region. The same change was identified in 8 of 105 additional individuals with hemangioma and in 12 of 295 controls. Expression of FLT1 (165070) in hemangioma endothelial cells was markedly reduced, and KDR activity was increased, compared to controls. In normal endothelial cells, FLT1 transcription is dependent on NFAT (see, e.g., NFATC2; 600490) activation. Further studies indicated that low VEGFR1 expression in hemangioma cells was caused by reduced activity of a pathway involving ITGB1 (135630), TEM8 (ANTXR1; 606410), KDR, and NFAT. The KDR mutation was predicted to result in loss of function and disruption of the normal association of these molecules, leading to an increased risk for development of hemangioma.
Aiello, L. P., Pierce, E. A., Foley, E. D., Takagi, H., Chen, H., Riddle, L., Ferrara, N., King, G. L., Smith, L. E. H. Suppression of retinal neovascularization in vivo by inhibition of vascular endothelial growth factor (VEGF) using soluble VEGF-receptor chimeric proteins. Proc. Nat. Acad. Sci. 92: 10457-10461, 1995. [PubMed: 7479819] [Full Text: https://doi.org/10.1073/pnas.92.23.10457]
Albuquerque, R. J. C., Hayashi, T., Cho, W. G., Kleinman, M. E., Dridi, S., Takeda, A., Baffi, J. Z., Yamada, K., Kaneko, H., Green, M. G., Chappell, J., Wilting, J., and 12 others. Alternatively spliced vascular endothelial growth factor receptor-2 is an essential endogenous inhibitor of lymphatic vessel growth. Nature Med. 15: 1023-1030, 2009. [PubMed: 19668192] [Full Text: https://doi.org/10.1038/nm.2018]
Autiero, M., Waltenberger, J., Communi, D., Kranz, A., Moons, L., Lambrechts, D., Kroll, J., Plaisance, S., De Mol, M., Bono, F., Kliche, S., Fellbrich, G., and 16 others. Role of PlGF in the intra- and intermolecular cross talk between the VEGF receptors Flt1 and Flk1. Nature Med. 9: 936-943, 2003. [PubMed: 12796773] [Full Text: https://doi.org/10.1038/nm884]
Basu, A., Hoerning, A., Datta, D., Edelbauer, M., Stack, M. P., Calzadilla, K., Pal, S., Briscoe, D. M. Cutting edge: vascular endothelial growth factor-mediated signaling in human CD45RO+ CD4+ T cells promotes Akt and ERK activation and costimulates IFN-gamma production. J. Immun. 184: 545-549, 2010. [PubMed: 20008289] [Full Text: https://doi.org/10.4049/jimmunol.0900397]
Basu, S., Nagy, J. A., Pal, S., Vasile, E., Eckelhoefer, I. A., Bliss, V. S., Manseau, E. J., Dasgupta, P. S., Dvorak, H. F., Mukhopadhyay, D. The neurotransmitter dopamine inhibits angiogenesis induced by vascular permeability factor/vascular endothelial growth factor. Nature Med. 7: 569-574, 2001. [PubMed: 11329058] [Full Text: https://doi.org/10.1038/87895]
Beck, B., Driessens, G., Goossens, S., Youssef, K. K., Kuchnio, A., Caauwe, A., Sotiropoulou, P. A., Loges, S., Lapouge, G., Candi, A., Mascre, G., Drogat, B., Dekoninck, S., Haigh, J. J., Carmeliet, P., Blanpain, C. A vascular niche and a VEGF-Nrp1 loop regulate the initiation and stemness of skin tumours. Nature 478: 399-403, 2011. [PubMed: 22012397] [Full Text: https://doi.org/10.1038/nature10525]
Benedito, R., Rocha, S. F., Woeste, M., Zamykal, M., Radtke, F., Casanovas, O., Duarte, A., Pytowski, B., Adams, R. H. Notch-dependent VEGFR3 upregulation allows angiogenesis without VEGF-VEGFR2 signalling. Nature 484: 110-114, 2012. [PubMed: 22426001] [Full Text: https://doi.org/10.1038/nature10908]
Bleyl, S., Nelson, L., Odelberg, S. J., Ruttenberg, H. D., Otterud, B., Leppert, M., Ward, K. A gene for familial total anomalous pulmonary venous return maps to chromosome 4p13-q12. Am. J. Hum. Genet. 56: 408-415, 1995. [PubMed: 7847375]
Cariboni, A., Andre, V., Chauvet, S., Cassatella, D., Davidson, K., Caramello, A., Fantin, A., Bouloux, P., Mann, F., Ruhrberg, C. Dysfunctional SEMA3E signaling underlies gonadotropin-releasing hormone neuron deficiency in Kallmann syndrome. J. Clin. Invest. 125: 2413-2428, 2015. [PubMed: 25985275] [Full Text: https://doi.org/10.1172/JCI78448]
Ding, B.-S., Nolan, D. J., Butler, J. M., James, D., Babazadeh, A. O., Rosenwaks, Z., Mittal, V., Kobayashi, H., Shido, K., Lyden, D., Sato, T. N., Rabbany, S. Y., Rafii, S. Inductive angiocrine signals from sinusoidal endothelium are required for liver regeneration. Nature 468: 310-315, 2010. [PubMed: 21068842] [Full Text: https://doi.org/10.1038/nature09493]
Folkman, J. Antiangiogenic gene therapy. Proc. Nat. Acad. Sci. 95: 9064-9066, 1998. [PubMed: 9689032] [Full Text: https://doi.org/10.1073/pnas.95.16.9064]
Fong, G.-H., Rossant, J., Gertsenstein, M., Breitman, M. L. Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature 376: 66-70, 1995. [PubMed: 7596436] [Full Text: https://doi.org/10.1038/376066a0]
Fulton, A. B., Hansen, R. M., Petersen, R. A., Vanderveen, D. K. The rod photoreceptors in retinopathy of prematurity: an electroretinographic study. Arch. Ophthal. 119: 499-505, 2001. [PubMed: 11296015] [Full Text: https://doi.org/10.1001/archopht.119.4.499]
Gogat, K., Le Gat, L., Van Den Berghe, L., Marchant, D., Kobetz, A., Gadin, S., Gasser, B., Quere, I., Abitbol, M., Menasche, M. VEGF and KDR gene expression during human embryonic and fetal eye development. Invest. Ophthal. Vis. Sci. 45: 7-14, 2004. [PubMed: 14691147] [Full Text: https://doi.org/10.1167/iovs.02-1096]
Greenberg, J. I., Shields, D. J., Barillas, S. G., Acevedo, L. M., Murphy, E., Huang, J., Scheppke, L., Stockmann, C., Johnson, R. S., Angle, N., Cheresh, D. A. A role for VEGF as a negative regulator of pericyte function and vessel maturation. Nature 456: 809-813, 2008. Note: Erratum: Nature 457: 1168 only, 2009. [PubMed: 18997771] [Full Text: https://doi.org/10.1038/nature07424]
Huber, T. L., Kouskoff, V., Fehling, H. J., Palis, J., Keller, G. Haemangioblast commitment is initiated in the primitive streak of the mouse embryo. Nature 432: 625-630, 2004. [PubMed: 15577911] [Full Text: https://doi.org/10.1038/nature03122]
Jin, D. K., Shido, K., Kopp, H.-G., Petit, I., Shmelkov, S. V., Young, L. M., Hooper, A. T., Amano, H., Avecilla, S. T., Heissig, B., Hattori, K., Zhang, F., and 10 others. Cytokine-mediated deployment of SDF-1 induces revascularization through recruitment of CXCR4+ hemangiocytes. Nature Med. 12: 557-567, 2006. Note: Erratum: Nature Med. 12: 978 only, 2006. [PubMed: 16648859] [Full Text: https://doi.org/10.1038/nm1400]
Jinnin, M., Medici, D., Park, L., Limaye, N., Liu, Y., Boscolo, E., Bischoff, J., Vikkula, M., Boye, E., Olsen, B. R. Suppressed NFAT-dependent VEGFR1 expression and constitutive VEGFR2 signaling in infantile hemangioma. Nature Med. 14: 1236-1246, 2008. [PubMed: 18931684] [Full Text: https://doi.org/10.1038/nm.1877]
Kendall, R. L., Wang, G., Thomas, K. A. Identification of a natural soluble form of the vascular endothelial growth factor receptor, FLT-1, and its heterodimerization with KDR. Biochem. Biophys. Res. Commun. 226: 324-328, 1996. [PubMed: 8806634] [Full Text: https://doi.org/10.1006/bbrc.1996.1355]
Maghsoudlou, A., Meyer, R. D., Rezazadeh, K., Arafa, E., Pudney, J., Hartsough, E., Rahimi, N. RNF121 inhibits angiogenic growth factor signaling by restricting cell surface expression of VEGFR-2. Traffic 17: 289-300, 2016. [PubMed: 26602861] [Full Text: https://doi.org/10.1111/tra.12353]
Mammoto, A., Connor, K. M., Mammoto, T., Yung, C. W., Huh, D., Aderman, C. M., Mostoslavsky, G., Smith, L. E. H., Ingber, D. E. A mechanosensitive transcriptional mechanism that controls angiogenesis. Nature 457: 1103-1108, 2009. [PubMed: 19242469] [Full Text: https://doi.org/10.1038/nature07765]
Matsumoto, K., Yoshitomi, H., Rossant, J., Zaret, K. S. Liver organogenesis promoted by endothelial cells prior to vascular function. Science 294: 559-563, 2001. [PubMed: 11577199] [Full Text: https://doi.org/10.1126/science.1063889]
Matthews, W., Jordan, C. T., Gavin, M., Jenkins, N. A., Copeland, N. G., Lemischka, I. R. A receptor tyrosine kinase cDNA isolated from a population of enriched primitive hematopoietic cells and exhibiting close genetic linkage to c-kit. Proc. Nat. Acad. Sci. 88: 9026-9030, 1991. [PubMed: 1717995] [Full Text: https://doi.org/10.1073/pnas.88.20.9026]
Millauer, B., Shawver, L. K., Plate, K. H., Risau, W., Ullrich, A. Glioblastoma growth inhibited in vivo by a dominant-negative Flk-1 mutant. Nature 367: 576-579, 1994. [PubMed: 8107827] [Full Text: https://doi.org/10.1038/367576a0]
Millauer, B., Wizigmann-Voos, S., Schnurch, H., Martinez, R., Moller, N. P. H., Risau, W., Ullrich, A. High affinity VEGF binding and developmental expression suggest Flk-1 as a major regulator of vasculogenesis and angiogenesis. Cell 72: 835-846, 1993. [PubMed: 7681362] [Full Text: https://doi.org/10.1016/0092-8674(93)90573-9]
Niethammer, A. G., Xiang, R., Becker, J. C., Wodrich, H., Pertl, U., Karsten, G., Eliceiri, B. P., Reisfeld, R. A. A DNA vaccine against VEGF receptor 2 prevents effective angiogenesis and inhibits tumor growth. Nature Med. 8: 1369-1375, 2002. [PubMed: 12415261] [Full Text: https://doi.org/10.1038/nm1202-794]
Nozaki, M., Sakurai, E., Raisler, B. J., Baffi, J. Z., Witta, J., Ogura, Y., Brekken, R. A., Sage, E. H., Ambati, B. K., Ambati, J. Loss of SPARC-mediated VEGFR-1 suppression after injury reveals a novel antiangiogenic activity of VEGF-A. J. Clin. Invest. 116: 422-429, 2006. [PubMed: 16453023] [Full Text: https://doi.org/10.1172/JCI26316]
Plate, K. H., Breier, G., Millauer, B., Ullrich, A., Risau, W. Up-regulation of vascular endothelial growth factor and its cognate receptors in a rat glioma model of tumor angiogenesis. Cancer Res. 53: 5822-5827, 1993. [PubMed: 7694795]
Qi, J. H., Ebrahem, Q., Moore, N., Murphy, G., Claesson-Welsh, L., Bond, M., Baker, A., Anand-Apte, B. A novel function for tissue inhibitor of metalloproteinases-3 (TIMP3): inhibition of angiogenesis by blockage of VEGF binding to VEGF receptor-2. Nature Med. 9: 407-415, 2003. [PubMed: 12652295] [Full Text: https://doi.org/10.1038/nm846]
Quinn, T. P., Peters, K. G., De Vries, C., Ferrara, N., Williams, L. T. Fetal liver kinase 1 is a receptor for vascular endothelial growth factor and is selectively expressed in vascular endothelium. Proc. Nat. Acad. Sci. 90: 7533-7537, 1993. [PubMed: 8356051] [Full Text: https://doi.org/10.1073/pnas.90.16.7533]
Sait, S. N. J., Dougher-Vermazen, M., Shows, T. B., Terman, B. I. The kinase insert domain receptor gene (KDR) has been relocated to chromosome 4q11-q12. Cytogenet. Cell Genet. 70: 145-146, 1995. [PubMed: 7736781] [Full Text: https://doi.org/10.1159/000134081]
Sawamiphak, S., Seidel, S., Essmann, C. L., Wilkinson, G. A., Pitulescu, M. E., Acker, T., Acker-Palmer, A. Ephrin-B2 regulates VEGFR2 function in developmental and tumour angiogenesis. Nature 465: 487-491, 2010. [PubMed: 20445540] [Full Text: https://doi.org/10.1038/nature08995]
Shalaby, F., Rossant, J., Yamaguchi, T. P., Gertsenstein, M., Wu, X.-F., Breitman, M. L., Schuh, A. C. Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature 376: 62-65, 1995. [PubMed: 7596435] [Full Text: https://doi.org/10.1038/376062a0]
Shay-Salit, A., Shushy, M., Wolfovitz, E., Yahav, H., Breviario, F., Dejana, E., Resnick, N. VEGF receptor 2 and the adherens junction as a mechanical transducer in vascular endothelial cells. Proc. Nat. Acad. Sci. 99: 9462-9467, 2002. [PubMed: 12080144] [Full Text: https://doi.org/10.1073/pnas.142224299]
Spritz, R. A., Strunk, K. M., Lee, S.-T., Lu-Kuo, J. M., Ward, D. C., Le Paslier, D., Altherr, M. R., Dorman, T. E., Moir, D. T. A YAC contig spanning a cluster of human type III receptor protein tyrosine kinase genes (PDGFRA-KIT-KDR) in chromosome segment 4q12. Genomics 22: 431-436, 1994. [PubMed: 7528718] [Full Text: https://doi.org/10.1006/geno.1994.1405]
Stockmann, C., Doedens, A., Weidemann, A., Zhang, N., Takeda, N., Greenberg, J. I., Cheresh, D. A., Johnson, R. S. Deletion of vascular endothelial growth factor in myeloid cells accelerates tumorigenesis. Nature 456: 814-818, 2008. [PubMed: 18997773] [Full Text: https://doi.org/10.1038/nature07445]
Terman, B., Carrion, M., Eddy, R. L., Shows, T. B. Tyrosine kinase growth factor receptor (KDR) localized to chromosome 4. (Abstract) Cytogenet. Cell Genet. 58: 1890 only, 1991.
Terman, B. I., Carrion, M. E., Kovacs, E., Rasmussen, B. A., Eddy, R. L., Shows, T. B. Identification of a new endothelial cell growth factor receptor tyrosine kinase. Oncogene 6: 1677-1683, 1991. [PubMed: 1656371]
Terman, B. I., Jani-Sait, S., Carrion, M. E., Shows, T. B. The KDR gene maps to human chromosome 4q31.2-q32, a locus which is distinct from locations for other type III growth factor receptor tyrosine kinases. Cytogenet. Cell Genet. 60: 214-215, 1992. [PubMed: 1324138] [Full Text: https://doi.org/10.1159/000133341]
Tzima, E., Irani-Tehrani, M., Kiosses, W. B., Dejana, E., Schultz, D. A., Engelhardt, B., Cao, G., DeLisser, H., Schwartz, M. A. A mechanosensory complex that mediates the endothelial cell response to fluid shear stress. Nature 437: 426-431, 2005. [PubMed: 16163360] [Full Text: https://doi.org/10.1038/nature03952]
Walter, J. W., North, P. E., Waner, M., Mizeracki, A., Blei, F., Walker, J. W. T., Reinisch, J. F., Marchuk, D. A. Somatic mutation of vascular endothelial growth factor receptors in juvenile hemangioma. Genes Chromosomes Cancer 33: 295-303, 2002. [PubMed: 11807987] [Full Text: https://doi.org/10.1002/gcc.10028]
Yamashita, J., Itoh, H., Hirashima, M., Ogawa, M., Nishikawa, S., Yurugi, T., Naito, M., Nakao, K., Nishikawa, S.-I. Flk1-positive cells derived from embryonic stem cells serve as vascular progenitors. Nature 408: 92-96, 2000. [PubMed: 11081514] [Full Text: https://doi.org/10.1038/35040568]
Yang, L., Soonpaa, M. H., Adler, E. D., Roepke, T. K., Kattman, S. J., Kennedy, M., Henckaerts, E., Bonham, K., Abbott, G. W., Linden, R. M., Field, L. J., Keller, G. M. Human cardiovascular progenitor cells develop from a KDR(+) embryonic-stem-cell-derived population. Nature 453: 524-528, 2008. [PubMed: 18432194] [Full Text: https://doi.org/10.1038/nature06894]
Zhang, F., Zarkada, G., Han, J., Li, J., Dubrac, A., Ola, R., Genet, G., Boye, K., Michon, P., Kunzel, S. E., Camporez, J. P., Singh, A. K., Fong, G.-H., Simons, M., Tso, P., Fernandez-Hernando C., Shulman, G. I., Sessa, W. C., Eichmann, A. Lacteal junction zippering protects against diet-induced obesity. Science 361: 599-603, 2018. [PubMed: 30093598] [Full Text: https://doi.org/10.1126/science.aap9331]
Ziegler, B. L., Valtieri, M., Porada, G. A., De Maria, R., Muller, R., Masella, B., Gabbianelli, M., Casella, I., Pelosi, E., Bock, T., Zanjani, E. D., Peschle, C. KDR receptor: a key marker defining hematopoietic stem cells. Science 285: 1553-1558, 1999. [PubMed: 10477517] [Full Text: https://doi.org/10.1126/science.285.5433.1553]