Pericyte recruitment and functions in vivo. Studies of platelet-derived growth factor-B deficient embryos

Abstract

A functional vascular system is essential for tissue growth and maintenance, and the circulatory system is therefore the first operational organ of the vertebrate embryo. In conditions of pathological tissue growth, such as tumors, formation of new blood vessels is also required, and it is anticipated that prevention of blood vessel development in those settings might ameliorate the disease progress.The vessels are composed of an inner lining of endothelial cells (ECs) and an outer coat of pericytes (PCs), in capillaries, or vascular smooth muscle cells (vSMCs) in larger vessels.During blood vessel development, platelet-derived growth factor-B (PDGF-B) is expressed by ECs, while PCs and vSMCs express PDGF receptor-b (PDGFR-b), indicating paracrine signaling between the two cell types. Targeted gene disruption of PDGF-B or PDGFR-b, leads to cardiovascular, renal and hematopoietic defects. Previously it was shown that PDGF-B deficient embryos had a reduced recruitment of PCs along the blood vessels and developed micro-aneurysms at late gestation. Depending on the tissue examined, the reduction of PCs was ranging from almost complete to only marginal. In this study, we have tried to understand the mechanisms behind the tissue variabililty in PC recruitment in both the PDGF-B and PDGFR-b deficient embryos, and the cellular and molecular events preceeding the micro-aneurysm formation.It was concluded that PDGF-B/PDGFR-b signaling acts as a selective signal for PC/vSMC progenitors, possibly by stimulating the proliferation of already commited PCs and vSMCs. The tissue specific variable reduction of the PC/vSMC in the knock-out embryos could potentially be explained by differential capacity to expand the PC/vSMC progenitor population by other means than PDGF-B/PDGFR-b signaling, e.g. de novo formation of PC/vSMCs or the existance of parallell signaling pathways to PDGF-B/PDGFR-b.The almost complete lack of PCs in the brain of the PDGF-B and PDGFR-b deficient embryos allowed us to analyze the development of the EC compartment without the influence of PCs. In line with the hypothesized role of PCs in negative growth control of ECs, there was a prominent hyperproliferation of brain ECs in the PDGF-B and PDGFR-b knock-out embryos, which could be an important step towards micro-aneurysm formation.