Endothelium-specific platelet-derived growth factor-B ablation mimics diabetic retinopathy

Abstract

Loss of pericytes from the capillary wall is a hallmark of diabetic retinopathy, however, the pathogenic signi®cance of this phenomenon is unclear. In previous mouse gene knockout models leading to pericyte de®-ciency, prenatal lethality has so far precluded analysis of postnatal consequences in the retina. We now report that endothelium-restricted ablation of platelet-derived growth factor-B generates viable mice with extensive inter-and intra-individual variation in the density of pericytes throughout the CNS. We found a strong inverse correlation between pericyte density and the formation of a range of retinal microvascular abnormalities strongly reminiscent of those seen in diabetic humans. Proliferative retinopathy invariably developed when pericyte density was <50% of normal. Our data suggest that a reduction of the pericyte density is suf®cient to cause retinopathy in mice, implying that pericyte loss may also be a causal pathogenic event in human diabetic retinopathy.

The brain tumor microenvironment

“…This results in proliferation and migration of pericytes/VSM cells during maturation of vessels (Betsholtz, 2004;Hoch and Soriano, 2003). Studies show depletion of pdgfb specifically in the endothelium, results in significant pericyte deficiency in the vasculature (Bjarnegard et al, 2004;Enge et al, 2002) whilst similar depletion of pdgfb in hematopoetic or neuronal cells had no effect on the vasculature (Buetow et al, 2001;Enge et al, 2003). These interactions highlight the critical role of endothelium-derived PDGF in pericyte recruitment.…”

Substrates modified by advanced glycation end-products cause dysfunction and death in retinal pericytes by reducing survival signals mediated by platelet-derived growth factor

“…This finding is supported by the fact that PDGF isoforms are established survival factors for pericytes in other non-retinal vascular beds [25]. The role of this growth factor in diabetic retinopathy is also exemplified by the recent report that effective removal of PDGF-BB (as occurs in PDGF-BB null mice) causes depletion of retinal pericytes, an effect which is exacerbated when experimental diabetes is induced in this heterozygous transgenic model [13,29]. During diabetes, AGE cross-linking of the BM may serve to reduce effective transmittance of PDGF isoforms to the pericyte, whether they are derived from serum or secreted by endothelium and/or cells of the retinal neuropile.…”

“…In combination with the low replicative capacity of retinal pericytes both in health and during diabetes, AGE-mediated depletion of BM-immobilised growth factors has important survival implications for pericytes and the progression of diabetic retinopathy [25,28,29]. The current study adopted an in vitro model by exposing retinal pericytes to a well-characterised and defined AGE-modified substrate and investigating pericyte replicative capacity and apoptotic death.…”

Standard of care therapy for malignant glioma and its effect on tumor and stromal cells

“…A study that inhibited PDGF function in endothelial cells showed a decrease in pericyte recruitment emphasizing the importance of PDGF signaling in promoting stable vessel formation (Enge et al, 2002;Bjarnegard et al, 2004). Another pericyte-endothelial cell interaction involves the Tie2 receptor expressed by endothelial cells and its ligand Ang1 expressed by adjacent pericytes.…”