Pericytes, Microvasular Dysfunction, and Chronic Rejection

Abstract

Chronic rejection of transplanted organs remains the main obstacle in the long-term success of organ transplantation. Thus, there is a persistent quest for development of anti-chronic rejection therapies and identification of novel molecular and cellular targets. One of the potential targets is the pericytes, the mural cells of microvessels, which regulate microvascular permeability, development and maturation by controlling endothelial cell functions and regulating tissue fibrosis and inflammatory response. In this review we discuss the potential of targeting pericytes in development of microvasular dysfunction and the molecular pathways involved in regulation of pericyte activities for anti-chronic rejection intervention.

Lung Pericytes and Resident Fibroblasts

“…3,5,17,20,36,41 ABCG2-expressing, or lineagemarked, NG2 À MSCs express mostly the same genes at similar levels as NG2 þ cells, but lower levels of Table 2). Dashed lines indicate additional hypotheses for the origins of a-smooth muscle actin (a-SMA) À pathogenic fibroblasts in injured lung.…”

“…5,6,18 The receptor, PDGFR-b, marks pericytes and establishes their interactions with endothelial cells. Endothelial cells produce its ligand PDGF-B when sprouting, to which the pericytes respond by proliferating and migrating to attach to and cover the growing vessel.…”

“…The primary consequence of PDGF pathway defects is vascular dysfunction, with endothelial hyperplasia, poor vessel integrity, microcapillary aneurysms, and loss of pericyte coverage in the lung and other organs. 2,3,5,19,44 Furthermore, the endothelial-pericyte dependence on PDGF-B to prevent vascular leakage increases during sustained lung inflammation and is required for angiopoietin-1 (Ang-1) to help stabilize the endothelium. 49 Paracrine signaling by Ang-1 from pericytes through its receptor Tie-2 on endothelial cells generates a reciprocal interaction to the PDGF pathway.…”

“…3,5,18,46 Unlike the PDGF pathway, disconnecting Ang-1 from Tie-2 does not interfere with pericyte positioning or reduce their vascular coverage, although it does alter the number and proportions of vessels during embryonic development. 3,5,43 Instead, targeted Ang-1 deficiency exacerbated fibrosis in response to physical damage or vascular stress, implying that the Ang-1/Tie2 connection between pericytes and endothelial cells regulates their coordinated response to injury. 3,43 Figure 3 Collagen (Col) 1 expression distinguishes between immune and matrix-oriented lung fibroblasts.…”

“…However, the TGF-b pathway is so broadly engaged in development and pathogenesis in all organs, including its potential to stimulate opposing effects in angiogenesis, that without data from inducible, cell typee specific inhibition experiments, it remains problematic to assign discrete, TGF-bedependent roles to lung pericytes in vascular biology. 3,5,18,53 Pericytes sense vasoactive molecules and neurotransmitters, and one of their first proposed functions was to control blood flow by regulating the diameter of capillary vessels. 3 Ang-1 overexpression did increase capillary diameter, although whether periyctes could exert sufficient mechanical force to squeeze or stretch a capillary structure has been debated.…”