Animal Models Mimicking Retinal Pericyte Loss

As noted earlier, the PDGF-B/ß-receptor and the Ang/Tie-2 system are important in the recruitment of pericytes to the retinal vasculature. Mice with modifications of these factors are suitable to understand the vascular consequences of pericyte deficiencies. Other factors like VEGF and IGF-1 can play a critical role in the survival of retinal vessels and in the pathogenesis of proliferative diabetic retinopathy.

PDGF-B-PDGF-SSR

Genetic ablation of PDGF-B has major effects on the brain microvasculature. Studies using PDGF-B deficient mouse embryos demonstrated a complete lack of microvascular pericytes and the development of numerous capillary microaneurysms that ruptured at birth, when blood pressure increases. Endothelial cells of sprouting capillaries in the mutant mice appeared to be unable to attract PDGFR-b-positive pericyte progenitor cells (98). Hemorrhages are also prevalent in mice with a deletion of the cognate receptor PDGFR-b, and in mice in which the proper recruitment of pericytes was abolished by an antagonistic mAb against PDGFR-beta. The perinatal death of these animals precluded retinal studies. However, as some of the lesions in vessels of affected mice were reminiscent of early retinal lesions in diabetes, heterozygous PDGF-B mice were used to study the retinal vasculature. The retinae showed a 28% reduction in the number of pericytes compared to wildtype littermates and an increase in acellular capillaries during adulthood, implying that pericytes have survival-promoting functions for established retinal capillary. This concept was supported by the findings that pericyte dropout in PDGF-B deficient mice was further aggravated when chronic hyperglycemia was superimposed (99).

Since the perinatal lethality of homozygous PDGF-B mice precluded vascular studies of the retina, mice with an endothelium-restricted ablation of PDGF-B were created to study pericyte recruitment, vasoregression, and proliferation. The level of pericyte coverage was determined in different areas of the brain and in the retina. It was observed that pericyte loss up to 50% was accompanied by vasoregression in the retina, whereas pericyte deficits exceeding 50% induced retinal vasoproliferations mimicking proliferative diabetic retinopathy. Thus, there is an obvious discrepancy between hyperglycemiainduced pericyte loss > 50% and a genetically induced loss.

ANGIOPOIETIN-TIE

The Angiopoietin-Tie family consists of several members of ligands (Ang-1–4) and of receptor tyrosine kinases (Tie-1/2). While Ang-1–4 act via ligation to Tie-2, no active ligand for Tie-1 has been unequivocally identified. Tie-2 has been identified on cells important for vascular cell survival and angiogenesis, including pericytes (54)].

The interaction of Ang-1 with Tie-2 is crucial for the timely and coordinated recruitment of pericytes to the developing vascular system. The concept that angiopoietin-1 acting via the receptor tyrosine kinase Tie-2 determines endothelial cell survival, sprouting, vessel remodeling, and stabilization though the recruitment of pericytes still hold true for retinal vessels. The activity of Tie-2 is differentially regulated as the natural antagonist of Ang-1, angiopoietin-2 (Ang-2) inhibits the phosphorylation of Tie-2, induced by Ang-1. Ang-2 cooperates with VEGF to induce angiogenesis, while Ang-2 in absence of VEGF induces capillary regression (100). To assess the pathogenetic role