Targeting Endothelium-Pericyte Cross Talk by Inhibiting VEGF Receptor Signaling Attenuates Kidney Microvascular Rarefaction and Fibrosis

Abstract

Microvascular pericytes and perivascular fibroblasts have recently been identified as the source of scar-producing myofibroblasts that appear after injury of the kidney. We show that cross talk between pericytes and endothelial cells concomitantly dictates development of fibrosis and loss of microvasculature after injury. When either platelet-derived growth factor receptor (R)-␤ signaling in pericytes or vascular endothelial growth factor (VEGF)R2 signaling in endothelial cells was blocked by circulating soluble receptor ectodomains, both fibrosis and capillary rarefaction were markedly attenuated during progressive kidney injury. Blockade of either receptor-mediated signaling pathway prevented pericyte differentiation and proliferation, but VEGFR2 blockade also attenuated recruitment of inflammatory macrophages throughout disease progression. Whereas injury down-regulated angiogenic VEGF164, the dys-angiogenic isomers VEGF120 and VEGF188 were up-regulated, suggesting that pericyte-myofibroblast differentiation triggers endothelial loss by a switch in secretion of VEGF isomers. These findings link fibrogenesis inextricably with microvascular rarefaction for the first time, add new significance to fibrogenesis, and identify novel therapeutic targets. (Am J Pathol 2011, 178:911-923;

Pericytes, mesenchymal stem cells and their contributions to tissue repair

“…PDGFRβ/PDGF-BB is the main signalling pathway mediating pericyte recruitment during vessel development (Hellstrom et al, 1999). This same pathway has been reported in the recruitment of pericytes to injured tissue, where they eventually contribute to fibrosis in organs such as the lung (Hung et al, 2013) and kidney (Humphreys et al, 2010;Lin et al, 2011;Schrimpf et al, 2012). Activated pericytes have been shown to detach from local capillaries, migrate to the site of injury and differentiate into myofibroblasts (Goritz et al, 2011;Lin et al, 2011;Ren et al, 2013).…”

“…This same pathway has been reported in the recruitment of pericytes to injured tissue, where they eventually contribute to fibrosis in organs such as the lung (Hung et al, 2013) and kidney (Humphreys et al, 2010;Lin et al, 2011;Schrimpf et al, 2012). Activated pericytes have been shown to detach from local capillaries, migrate to the site of injury and differentiate into myofibroblasts (Goritz et al, 2011;Lin et al, 2011;Ren et al, 2013). However, the recruitment of pericytes following injury and their collagen-producing capacity may be dependent on both the type of injury and the tissue under investigation (Birbrair et al, 2014a;Nakagomi et al, 2011).…”

Concise Review: Wharton's Jelly: The Rich, but Enigmatic, Source of Mesenchymal Stromal Cells

“…One possible mechanism for this, as mentioned above, is through the PDGF/PDGFRβ axis. Signaling through this pathway results in a potent chemotactic and mitogenic response seen in pericyte recruitment, both during development 69, 70, and following tissue injury 71, 72. In cell culture, it has been reported that amniotic epithelial cells produce PDGF‐B 73, 74, and therefore, could potentially serve as a stimulus for perivascular migration in vivo.…”

Renal Allograft Fibrosis: Biology and Therapeutic Targets

“…Kidney endothelial cells may promote fibrosis by expression of ECM, as suggested in experimental diabetic nephropathy (206) or via a crosstalk with interstitial cells (207). Apart from proangiogenic growth factors (150), several proteins have been suggested to play a role in endothelial cell remodeling leading to fibrosis including ephrin-B (208), Crim-1 (209), Id proteins (210), miR-126 (211), and the glycocalyx of glomerular endothelial cells (212).…”