Effects of PDGF-B gene inactivation in endothelial cell

Abstract

Platelet-derived growth factor-B (PDGF-B) is expressed by endothelial cells, neurons, macrophages and platelets. The relative importance of these cellular PDGF-B sources in vivo has been addressed by the creation of a conditional PDGF-B allele, which in the presence of a specific recombinase can be silenced in different tissues. Endothelium-specific PDGF-B ablation leads to defective pericyte recruitment to growing and branching blood vessels. In the embryo, this results in abnormalities such as kidney glomeruli devoid of mesangial cells, heart dilation, placenta abnormalities, spontaneous bleedings, microaneurysms and lowered capillary density in the central nervous system (CNS). All these changes are common to both the endothelium-specific and the full PDGF-B knock-out, but the former presents a variable and slightly milder phenotype, due to an incomplete recombination process. The resulting cellular mosaicism allows for postnatal survival, and thereby studies of adult PDGF-B functions.Many of the embryonic phenotypes seen in endothelium-specific PDGF-B knock-out mice normalized postnatally, but certain pathological changes persisted and even became aggravated in the adult animals. We conclude that: Endothelial cells are the most important source of PDGF-B, and this source is crucial for pericyte recruitment. The pericyte density directly reflects the level of endothelium-produced PDGF-B. The defective pericyte recruitment is probably the cause of all organ defects seen in the endothelium-specific PDGF-B knock-outs, including placenta and heart defects. The pericyte deficiency leads to a spectrum of vascular defects which mimics diabetic micro-angiopathy. The retina is particularly sensitive to pericyte deficiency. When the density falls below 50% of normal, the retinopathy changes from a non-proliferative to a proliferative state, similar to the progression at diabetic retinopathy. Endothelium-derived PDGF-B is important for kidney glomerular function as endothelium-specific PDGF-B knock-outs develop proteinuria in morphologically normal kidneys