Abstract
Vascular endothelial growth factor receptor (VEGFR)-1 exists in different forms, derived from alternative splicing of the same gene. In addition to the transmembrane form, endothelial cells produce a soluble VEGFR-1 (sVEGFR-1) isoform, whereas non-endothelial cells produce both sVEGFR-1 and a different soluble molecule, known as soluble fms-like tyrosine kinase (sFlt)1-14. By binding members of the vascular endothelial growth factor (VEGF) family, the soluble forms reduce the amounts of VEGFs available for the interaction with their transmembrane receptors, thereby negatively regulating VEGFR-mediated signaling. In agreement with this activity, high levels of circulating sVEGFR-1 or sFlt1-14 are associated with different pathological conditions involving vascular dysfunction. Moreover, sVEGFR-1 and sFlt1-14 have an additional role in angiogenesis: they are deposited in the endothelial cell and pericyte extracellular matrix, and interact with cell membrane components. Interaction of sVEGFR-1 with α5β1 integrin on endothelial cell membranes regulates vessel growth, triggering a dynamic, pro-angiogenic phenotype. Interaction of sVEGFR-1/sFlt1-14 with cell membrane glycosphingolipids in lipid rafts controls kidney cell morphology and glomerular barrier functions. These cell–matrix contacts represent attractive novel targets for pharmacological intervention in addition to those addressing interactions between VEGFs and their receptors.
Highlights
During embryo development, cells from mesoderm differentiate into pluripotent hemangioblasts, and into angioblasts and endothelial cells, in a process called vasculogenesis
The role of transmembrane Vascular endothelial growth factor receptor (VEGFR)-1 in the angiogenic process has been underestimated for a long period, probably because of its dispensability as tyrosine kinase receptor during embryonic development
SVEGFR-1/soluble fms-like tyrosine kinase (sFlt)-1 are likely to have an active role in angiogenesis, which is exerted by binding molecules different from vascular endothelial growth factor (VEGF)
Summary
Cells from mesoderm differentiate into pluripotent hemangioblasts, and into angioblasts and endothelial cells, in a process called vasculogenesis. High levels of sVEGFR-1 or sFlt are found in pathological conditions involved in vascular dysfunction, as discussed below These observations restrict the hypothesis that VEGFR-1 acts as a VEGF-sink/transmembrane receptor inhibitor to soluble VEGFR-1 isoforms only. Since VEGF-A binding region is present in the soluble isoforms as well, the highest inhibition of VEGF-A signaling by the transmembrane form can be ascribed, at least in part, to a greater ability to heterodimerize with VEGFR-2, reducing VEGF-A signaling mediated by the latter receptor In agreement with this hypothesis, the same mouse model produced in a different genetic background, and expressing higher VEGFR-2 levels than the previous strain, led to the survival of most animals [18]. It could not be ruled out that other differences between the two mouse strains (e.g., in factors involved in cell-to-matrix interactions) contributed to a reversion of the mouse phenotype back to normal
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