HGNC Approved Gene Symbol: VCAM1
Cytogenetic location: 1p21.2 Genomic coordinates (GRCh38): 1:100,719,742-100,739,045 (from NCBI)
Vascular cell adhesion molecule-1, a cell surface glycoprotein expressed by cytokine-activated endothelium, mediates the adhesion of monocytes and lymphocytes. In inflammatory conditions and in cardiac allografts undergoing rejection, VCAM1 is upregulated in endothelium of postcapillary venules. Arterial expression of VCAM1 is also found in experimental models of atherosclerosis in the rabbit (summary by Cybulsky et al., 1991).
Cybulsky et al. (1991) demonstrated that VCAM1 is present in single copy in the human genome and contains 9 exons spanning about 25 kb of DNA. At least 2 different VCAM1 precursors can be generated from the human gene as a result of alternative mRNA splicing events, which include or exclude exon 5.
Cybulsky et al. (1991) mapped the VCAM1 gene to chromosome 1 by Southern analysis of somatic cell hybrids. A study of 2 hybrid lines carrying translocations involving chromosome 1 permitted regionalization to 1p34-p21. Fluorescence in situ hybridization to metaphase chromosomes further narrowed the localization to 1p32-p31. (Another endothelial leukocyte adhesion molecule, ELAM1 (131210), is located on chromosome 1, but on the long arm.)
Kumar et al. (1994) mapped the murine Vcam1 gene to chromosome 3 near Amy1.
In a review of molecular pathways controlling heart development, Olson and Srivastava (1996) cited studies indicating that deficiencies of the cell adhesion molecules VCAM and alpha-4 integrin (192975) result in epicardial dissolution and subsequent myocardial thinning.
Lu and Cyster (2002) studied the mechanisms that control localization of marginal zone B cells. They demonstrated that marginal zone B cells express elevated levels of the integrins LFA1 (see 153370/600065) and alpha-4 (192975)-beta-1 (135630), and that the marginal zone B cells bind to the ligands ICAM1 (147840) and VCAM1. These ligands are expressed within the marginal zone in a lymphotoxin-dependent manner. Combined inhibition of LFA1 and alpha-4-beta-1 causes a rapid and selective release of B cells from the marginal zone. Furthermore, lipopolysaccharide-triggered marginal zone B cell relocalization involves downregulation of integrin-mediated adhesion. Lu and Cyster (2002) concluded that their studies identified key requirements for marginal zone B cell localization and established a role for integrins in peripheral lymphoid tissue compartmentalization.
Garmy-Susini et al. (2005) demonstrated that integrin alpha-4-beta-1 and VCAM1 are expressed by proliferating but not quiescent endothelial cells and mural cells, respectively. Antagonists of this integrin-ligand pair blocked the adhesion of mural cells to proliferating endothelia in vitro and in vivo, thereby inducing apoptosis of endothelial cells and pericytes and inhibiting neovascularization. Garmy-Susini et al. (2005) concluded that integrin alpha-4-beta-1 and VCAM1 facilitate a critical cell-cell adhesion event required for survival of endothelial and mural cells during vascularization.
Garrison et al. (2005) described cotransin, a small molecule that inhibits protein translocation into the endoplasmic reticulum. Cotransin acts in a signal-sequence-discriminatory manner to prevent the stable insertion of select nascent chains (specifically VCAM1, and P-selectin, 173610) into the Sec61 translocation channel. Garrison et al. (2005) concluded that the range of substrates accommodated by the channel can be specifically and reversibly modulated by a cell-permeable small molecule that alters the interaction between signal sequences and the Sec61 complex. This has various implications for drug development.
Besemer et al. (2005) developed a very similar VCAM1 depressing agent, which they called CAM741. CAM741 works similar to cotransin in that it represses the biosynthesis of VCAM1 cells by blocking the process of cotranslational translocation, which is dependent on the signal peptide of VCAM1. CAM741 does not inhibit targeting of the VCAM1 nascent chains to the translocon channel but prevents translocation to the luminal side of the endoplasmic reticulum through a process that involves the translocon component Sec61-beta (609214). Consequently, the VCAM1 precursor protein is synthesized towards the cytosolic compartment of the cells, where it is degraded.
By in vivo selection, transcriptomic analysis, functional verification, and clinical validation, Minn et al. (2005) identified a set of genes that marks and mediates breast cancer metastasis to the lungs. Some of these genes serve dual functions, providing growth advantages both in the primary tumor and in the lung microenvironment. Others contribute to aggressive growth selectivity in the lung. Among the lung metastasis signature genes identified, several, including VCAM1, were functionally validated. Those subjects expressing the lung metastasis signature had a significantly poorer lung metastasis-free survival, but not bone metastasis-free survival, compared to subjects without the signature.
Campbell et al. (2006) found that increased serum levels of soluble VCAM1 predicted recurrent ischemic stroke (601367) in a study of 252 patients. A smaller but similar trend was noted for serum levels of N-terminal pro-B-type natriuretic peptide (NPPB; 600295). Patients in the highest quarters for both sVCAM1 and NT-proBNP levels had 3.6 times the risk of recurrent ischemic stroke compared to patients in the lowest quarters for both biologic markers.
By database analysis, Harris et al. (2008) identified a potential target sequence for miR126 (MIRN126; 611767), a microRNA selectively expressed in endothelial cells, in the 3-prime UTR of VCAM1. Transfection of human endothelial cells with antisense miR126 permitted an increase in TNF-alpha (TNF; 191160)-stimulated VCAM1 expression. Conversely, overexpression of the miR126 precursor increased miR126 levels and decreased VCAM1 expression. Decreasing endogenous miR126 levels increased leukocyte adherence to endothelial cells. Harris et al. (2008) concluded that miR126 inhibits VCAM1 expression.
Li et al. (2018) used advanced live imaging and a cell labeling system to perform high-resolution analyses of hematopoietic stem and progenitor cell (HSPC) homing in caudal hematopoietic tissue of zebrafish, equivalent to the fetal liver in mammals, and revealed the role of vascular architecture in the regulation of HSPC retention. Li et al. (2018) identified a VCAM1-positive macrophage-like niche cell population that patrols the inner surface of the venous plexus, interacts with HSPCs in an ITGA4 (192975)-dependent manner, and directs HSPC retention. These cells, which they called 'usher cells,' together with caudal venous capillaries and plexus, defined retention hotspots within the homing microenvironment.
Taylor et al. (2002) identified 33 SNPs in the VCAM1 locus. They then analyzed a subset of these SNPs in 51 cases of stroke in sickle cell disease (603903) patients derived from a single institution in Jamaica and in 51 matched controls. They found that the C variant allele of the nonsynonymous SNP 1238G-C, which results in a gly413-to-ala amino acid change (G413A), may be associated with protection from stroke (odds ratio = 0.35). Dover (2002) stated that sickle cell disease is not a single gene disorder and emphasized the need for further studies of the relationship of VCAM1 to strokes in this disorder.
Idelman et al. (2007) stated that VCAM1 transcription induction is highly dependent on cell and organ type and mode of stimulation by various transcription factors. The authors identified 8 VCAM1 promoter haplotypes comprising 13 SNPs previously identified by Taylor et al. (2002) in African Americans. Functional cellular expression studies in T cells stimulated by T-cell mitogens assessed the inducibility of expression of the different haplotypes. A -540A-G SNP (rs3783605) was found to gain an ETS2 (164740)-binding site, which was postulated by Idelman et al. (2007) to have functional importance.
Besemer, J., Harant, H., Wang, S., Oberhauser, B., Marquardt, K., Foster, C. A., Schreiner, E. P., de Vries, J. E., Dascher-Nadel, C., Lindley, I. J. D. Selective inhibition of cotranslational translocation of vascular cell adhesion molecule 1. (Letter) Nature 436: 290-293, 2005. [PubMed: 16015337] [Full Text: https://doi.org/10.1038/nature03670]
Campbell, D. J., Woodward, M., Chalmers, J. P., Colman, S. A., Jenkins, A. J., Kemp, B. E., Neal, B. C., Patel, A., MacMahon, S. W. Soluble vascular cell adhesion molecule 1 and N-terminal pro-B-type natriuretic peptide in predicting ischemic stroke in patients with cerebrovascular disease. Arch. Neurol. 63: 60-65, 2006. [PubMed: 16286536] [Full Text: https://doi.org/10.1001/archneur.63.1.noc50221]
Cybulsky, M., Fries, J. W., Williams, A. J., Sultan, P., Eddy, R. L., Byers, M. G., Shows, T. B., Gimbrone, M. A., Jr., Collins, T. The human VCAM1 gene is assigned to chromosome 1p31-p32. (Abstract) Cytogenet. Cell Genet. 58: 1852, 1991.
Cybulsky, M. I., Fries, J. W. U., Williams, A. J., Sultan, P., Eddy, R., Byers, M., Shows, T., Gimbrone, M. A., Jr., Collins, T. Gene structure, chromosomal location, and basis for alternative mRNA splicing of the human VCAM1 gene. Proc. Nat. Acad. Sci. 88: 7859-7863, 1991. [PubMed: 1715583] [Full Text: https://doi.org/10.1073/pnas.88.17.7859]
Dover, G. J. SS disease is not a single gene disorder. (Letter) Blood 100: 4255 only, 2002.
Garmy-Susini, B., Jin, H., Zhu, Y., Sung, R.-J., Hwang, R., Varner, J. Integrin alpha-4-beta-1--VCAM-1--mediated adhesion between endothelial and mural cells is required for blood vessel maturation. J. Clin. Invest. 115: 1542-1551, 2005. [PubMed: 15902308] [Full Text: https://doi.org/10.1172/JCI23445]
Garrison, J. L., Kunkel, E. J., Hedge, R. S., Taunton, J. A substrate-specific inhibitor of protein translocation into the endoplasmic reticulum. (Letter) Nature 436: 285-289, 2005. [PubMed: 16015336] [Full Text: https://doi.org/10.1038/nature03821]
Harris, T. A., Yamakuchi, M., Ferlito, M., Mendell, J. T., Lowenstein, C. J. MicroRNA-126 regulates endothelial expression of vascular cell adhesion molecule 1. Proc. Nat. Acad. Sci. 105: 1516-1521, 2008. [PubMed: 18227515] [Full Text: https://doi.org/10.1073/pnas.0707493105]
Idelman, G., Taylor, J. G., Tongbai, R., Chen, R. A., Haggerty, C. M., Bilke, S., Chanock, S. J., Gardner, K. Functional profiling of uncommon VCAM1 promoter polymorphisms prevalent in African American populations. Hum. Mutat. 28: 824-829, 2007. [PubMed: 17431880] [Full Text: https://doi.org/10.1002/humu.20523]
Kumar, A. G., Dai, X. Y., Kozak, C. A., Mims, M. P., Gotto, A. M., Ballantyne, C. M. Murine VCAM-1: molecular cloning, mapping, and analysis of a truncated form. J. Immun. 153: 4088-4098, 1994. [PubMed: 7523515]
Li, D., Xue, W., Li, M., Dong, M., Wang, J., Wang, X., Li, X., Chen, K., Zhang, W., Wu, S., Zhang, Y., Gao, L., Chen, Y., Chen, J., Zhou, B. O., Zhou, Y., Yao, X., Li, L., Wu, D., Pan, W. VCAM-1+ macrophages guide the homing of HSPCs to a vascular niche. Nature 564: 119-124, 2018. [PubMed: 30455424] [Full Text: https://doi.org/10.1038/s41586-018-0709-7]
Lu, T. T., Cyster, J. G. Integrin-mediated long-term B cell retention in the splenic marginal zone. Science 297: 409-412, 2002. [PubMed: 12130787] [Full Text: https://doi.org/10.1126/science.1071632]
Minn, A. J., Gupta, G. P., Siegel, P. M., Bos, P. D., Shu, W., Giri, D. D., Viale, A., Olshen, A. B., Gerald, W. L., Massague, J. Genes that mediate breast cancer metastasis to lung. Nature 436: 518-524, 2005. [PubMed: 16049480] [Full Text: https://doi.org/10.1038/nature03799]
Olson, E., Srivastava, D. Molecular pathways controlling heart development. Science 272: 671-676, 1996. [PubMed: 8614825] [Full Text: https://doi.org/10.1126/science.272.5262.671]
Taylor, J. G., VI, Tang, D. C., Savage, S. A., Leitman, S. F., Heller, S. I., Serjeant, G. R., Rodgers, G. P., Chanock, S. J. Variants in the VCAM1 gene and risk for symptomatic stroke in sickle cell disease. Blood 100: 4303-4309, 2002. [PubMed: 12393616] [Full Text: https://doi.org/10.1182/blood-2001-12-0306]