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Physiological Role of Vascular Endothelial Growth Factors as Homeostatic Regulators

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The vascular endothelial growth factor (VEGF) family of proteins are key regulators of physiological systems. Originally linked with endothelial function, they have since become understood to be principal regulators of multiple tissues, both through their actions on vascular cells, but also through direct actions on other tissue types, including epithelial cells, neurons, and the immune system. The complexity of the five members of the gene family in terms of their different splice isoforms, differential translation, and specific localizations have enabled tissues to use these potent signaling molecules to control how they function to maintain their environment. This homeostatic function of VEGFs has been less intensely studied than their involvement in disease processes, development, and reproduction, but they still play a substantial and significant role in healthy control of blood volume and pressure, interstitial volume and drainage, renal and lung function, immunity, and signal processing in the peripheral and central nervous system. The widespread expression of VEGFs in healthy adult tissues, and the disturbances seen when VEGF signaling is inhibited support this view of the proteins as endogenous regulators of normal physiological function. This review summarizes the evidence and recent breakthroughs in understanding of the physiology that is regulated by VEGF, with emphasis on the role they play in maintaining homeostasis. © 2017 American Physiological Society. Compr Physiol 8:955‐979, 2018.

Figure 1. Figure 1. Schematic of the VEGF receptors. VEGFR1 and VEGFR2 both have seven IgG domains, and when they bind VEGF act as homodimers. The intracellular domain contains a kinase insert domain, and the receptors can heterodimerize. VEGFR3 is a similar receptor but is proteolytically cleaved during synthesis, and held together with a disulfine bond between IgG 4 and 5. The coreceptors NP1 and NP2 interact with the VEGF receptors to aid signaling, intracellular sorting, and recycling to the membrane. VEGF‐B and PlGF both bind only to VEGFR1, VEGF‐A binds both VEGFR1 and VEGFR2 and VEGF‐C, and VEGF‐D bind to VEGFR3, but when proteolytically processed increase their affinity for VEGFR2.
Figure 2. Figure 2. Splicing of the VEGF‐A gene. The eight exons are differentially spliced to form multiple isoforms in two primary families, the proangiogenic VEGF‐Axxx, which use the proximal splice site in exon 8, and the partial agonist VEGF‐Axxxb family, which can prevent VEGF‐Axxx‐mediated angiogenesis, but can signal to prevent cytotoxicity through partial activation of VEGFR2.
Figure 3. Figure 3. Coverage of endothelial fenestrations by glycocalyx. Induction of fenestrations has been shown by VEGF, and VEGF knockdown in the glomerulus reduces fenestrations in glomerular endothelial cells. The endothelial cells, including the fenestrations, are covered with a glycocalyx (imaged in (A) using electron tomography transmission electron microscopy) (). (B) In diabetes the glycocalyx is lost, but can be restored by treatment with VEGF‐A165b ().

Figure 1. Schematic of the VEGF receptors. VEGFR1 and VEGFR2 both have seven IgG domains, and when they bind VEGF act as homodimers. The intracellular domain contains a kinase insert domain, and the receptors can heterodimerize. VEGFR3 is a similar receptor but is proteolytically cleaved during synthesis, and held together with a disulfine bond between IgG 4 and 5. The coreceptors NP1 and NP2 interact with the VEGF receptors to aid signaling, intracellular sorting, and recycling to the membrane. VEGF‐B and PlGF both bind only to VEGFR1, VEGF‐A binds both VEGFR1 and VEGFR2 and VEGF‐C, and VEGF‐D bind to VEGFR3, but when proteolytically processed increase their affinity for VEGFR2.

Figure 2. Splicing of the VEGF‐A gene. The eight exons are differentially spliced to form multiple isoforms in two primary families, the proangiogenic VEGF‐Axxx, which use the proximal splice site in exon 8, and the partial agonist VEGF‐Axxxb family, which can prevent VEGF‐Axxx‐mediated angiogenesis, but can signal to prevent cytotoxicity through partial activation of VEGFR2.

Figure 3. Coverage of endothelial fenestrations by glycocalyx. Induction of fenestrations has been shown by VEGF, and VEGF knockdown in the glomerulus reduces fenestrations in glomerular endothelial cells. The endothelial cells, including the fenestrations, are covered with a glycocalyx (imaged in (A) using electron tomography transmission electron microscopy) (). (B) In diabetes the glycocalyx is lost, but can be restored by treatment with VEGF‐A165b ().
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David O. Bates, Nicholas Beazley‐Long, Andrew V. Benest, Xi Ye, Nikita Ved, Richard P. Hulse, Shaney Barratt, Maria J. Machado, Lucy F. Donaldson, Steven J. Harper, Maria Peiris‐Pages, Domingo J. Tortonese, Sebastian Oltean, Rebecca R. Foster. Physiological Role of Vascular Endothelial Growth Factors as Homeostatic Regulators. Compr Physiol 2018, 8: 955-979. doi: 10.1002/cphy.c170015