Lack of pericytes leads to endothelial hyperplasia and abnormal vascular morphogenesis

The association of pericytes (PCs) to newly formed blood vessels has been s uggested to regulate endothelial cell (EC) proliferation, survival, migrati on, differentiation, and vascular branching. Here, we addressed these issue s using PDGF-B- and PDGF receptor-beta (PDGFR-beta)-deficient mice as in vi vo models of brain angiogenesis in the absence of PCs. Quantitative morphol ogical analysis showed that these mutants have normal microvessel density, length, and number of branch points. However, absence of PCs correlates wit h endothelial hyperplasia, increased capillary diameter, abnormal EC shape and ultrastructure, changed cellular distribution of certain junctional pro teins and morphological signs of increased transendothelial permeability. B rain endothelial hyperplasia was observed already at embryonic day (E) 11.5 and persisted throughout development. From E 13.5, vascular endothelial gr owth factor-A (VEGF-A) and other genes responsive to metabolic stress becam e upregulated, suggesting that the abnormal microvessel architecture has sy stemic metabolic consequences. VEGF-A upregulation correlated temporally wi th the occurrence of vascular abnormalities in the placenta and dilation of the heart. Thus, although PC deficiency appears to have direct effects on EC number before E 13.5, the subsequent increased VEGF-A levels may further abrogate microvessel architecture, promote vascular permeability, and cont ribute to formation of the edematous phenotype observed in late gestation P DGF-B and PDGFR-beta knock out embryos.