VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia

Abstract

Vascular endothelial growth factor (VEGF-A) is a major regulator of blood vessel formation and function. It controls several processes in endothelial cells, such as proliferation, survival, and migration, but it is not known how these are coordinately regulated to result in more complex morphogenetic events, such as tubular sprouting, fusion, and network formation. We show here that VEGF-A controls angiogenic sprouting in the early postnatal retina by guiding filopodial extension from specialized endothelial cells situated at the tips of the vascular sprouts. The tip cells respond to VEGF-A only by guided migration; the proliferative response to VEGF-A occurs in the sprout stalks. These two cellular responses are both mediated by agonistic activity of VEGF-A on VEGF receptor 2. Whereas tip cell migration depends on a gradient of VEGF-A, proliferation is regulated by its concentration. Thus, vessel patterning during retinal angiogenesis depends on the balance between two different qualities of the extracellular VEGF-A distribution, which regulate distinct cellular responses in defined populations of endothelial cells.

miR‐342‐5p Is a Notch Downstream Molecule and Regulates Multiple Angiogenic Pathways Including Notch, Vascular Endothelial Growth Factor and Transforming Growth Factor β Signaling

“…In the early phase of angiogenesis, a part of ECs differentiate into tip cells with filopodia. VEGF gradient‐guided migration of tip cells is essential for angiogenesis 43. Although VEGFR signaling could promote EC migration through mitogen‐activated protein kinase and ERK, recent studies have highlighted the role of EndMT in tip cell differentiation and migration 6, 7, 44.…”

Influence of PECAM-1 ligand interactions on PECAM-1-dependent cell motility and filopodia extension

“…This concentration of PECAM‐1 in filopodial tips is consistent with previous reports demonstrating that VEGFR‐2 and VEGFR‐3, two proangiogenic surface receptors, are present in the filopodial extensions of endothelial tip cells (Gerhardt et al. 2003; Tammela et al. 2008).…”

Multi-scale Computational Models of Pro-angiogenic Treatments in Peripheral Arterial Disease

“…15,52 Cells do not typically proliferate and migrate simultaneously, and therefore both absolute concentration and relative gradient may play a role in the cellularlevel decision-making process. Both values are difficult or impossible to measure in vivo at the microenvironmental level, and we report predicted values for both in this study.…”

“…31 We have also shown that increased cell-surface receptor expression can significantly increase the magnitude of VEGF gradients. 24,31,32 The size of the gradient over 10 lm can be compared with the typical length of endothelial tip cells, approximately 30-50 lm, 15,52 to determine whether the gradient is steep enough to be sensed by the cell.…”

“…In in vitro studies, they increase survival, proliferation and migration of endothelial cells; 55 in vivo, they act as a chemoattractant and direct capillary growth. 15,20,52 In this study, we use the term VEGF to refer to the two most common protein products of the rat VEGF-A gene, VEGF 120 , and VEGF 164 (VEGF 121 and VEGF 165 , respectively, in humans). The difference between these two proteins is the ability of the longer isoform to bind to both glycosaminoglycans (GAGs) in the interstitial space and Neuropilin co-receptors on endothelial cells.…”