Roles for VEGF in the adult

Abstract

The role of VEGF during development and in pathology is well known, but its function in normal adult tissues is poorly understood. Adverse effects associated with the use of anti-angiogenic therapies targeting VEGF in human pathologies have begun to reveal potential functions of VEGF in quiescent vasculature. Further clues from expression studies of VEGF and its receptors in the adult, from the disease preeclampsia, and from experimental neutralization studies, have suggested that VEGF is involved in endothelial cell survival and fenestration, as well as in the signaling and maintenance of non-endothelial cells. The various biochemical properties of VEGF, and its interaction with other growth factors, may be an important point in determining whether VEGF functions as a maintenance factor versus an angiogenic factor. A thorough understanding of the function of VEGF in the adult may lead to more efficacious pro- and anti-angiogenic therapies.

Figure 1. Expression of VEGF and its receptors in the adult

VEGF expression is shown in adult VEGF-lacZ mice, which make a nuclear localized β-galacotosidase (β-gal) protein wherever VEGF is expressed. Blood vessels, where shown, were identified by immunohistochemistry using the pan-endothelial cell marker- CD31 (arrowheads). VEGF expression in the pericytes in retina (A, arrows), cardiac myocytes (B), choroid RPE layer (C, arrows), choroid plexus epithelium (D, arrows) overlying fenestrated blood vessels (D, arrowheads), aortic endothelium (E, arrows), inferior vena cava medial layer cells (F, arrows). VEGFR2 expression and activation in adult tissues as identified by (G) western blot for VEGFR2 of protein lysates from liver, kidney, adipose and lung (bottom panel) and for phosphorylated VEGFR2 (top panel) and by (H) immunohistochemistry of aorta for phosphorylated VEGFR2 (arrows). Abbreviations (C): ONL, outer nuclear layer, OS, outer segment, RPE, retinal pigmented epithelium, Chd, choroid. Reprinted from IOVS 2006, 47: 3135–3142 (C), Am J Pathol 2006, 168: 639–658 with permission from the American Society of Investigative Pathology (B, D–H), unpublished data D’Amore lab (A).

Figure 2

MRI FLAIR image showing focal lesions (arrows) associated with reversible focal leukoencephalopathy in a patient on Avastin. Taken with permission from N Engl J Med (2006) 354; 980–982, Copyright © 2006 Massachusetts Medical Society

Figure 3. Role of VEGF in vascular stability

Administration of SU5416, a tyrosine kinase inhibitor with selective inhibition of VEGFR, to rats by bronchiolar delivery results in enlargement of air spaces, indicative of emphysema (D) compared to vehicle (A). Adenoviral delivery of sVEGFR1 to adult mice (B, E) results in decreased vascular density in the thyroid (E) compared to vehicle delivery (B), and endotheliosis in the glomerulus in the kidney in pregnant rats (F) compared to vehicle delivery (C). Taken with permission from J Clin Invest (2000) 106; 1311–1319 (A, D), Am J Physiol Heart Circ Physiol (2006): H560-H576 (B, E), and J Clin Invest (2003) 11; 649–658 (C, F).

Figure 4. Neuroprotective role of VEGF in the eye

Addition of VEGF120 after 60 min of ischemic/reperfusion injury resulted in decreased cell death in the ganglion cell layer (GCL), and inner nuclear layer (INL) after 14 days (C) compared to addition of PBS only (B). Taken from Nishijima et al. AJP 2007 (IN PRESS) with permission from the American Society of Investigative Pathology.