The Role of Pericyte Detachment in Vascular Rarefaction

Abstract

Background: Pericytes surround endothelial cells at the perivascular interface. Signaling between endothelial cells and pericytes is crucial for capillary homeostasis, as pericytes stabilize vessels and regulate many microvascular functions. Recently it has been shown that pericytes are able to detach from the vascular wall and contribute to fibrosis by becoming scar-forming myofibroblasts in many organs including the kidney. At the same time, the loss of pericytes within the perivascular compartment results in vulnerable capillaries which are prone to instability, pathological angiogenesis, and, ultimately, rarefaction. Aims: This review will give an overview of pericyte-endothelial cell interactions, summarize the signaling pathways that have been identified to be involved in pericyte detachment from the vascular wall, and present pathological endothelial responses in the context of disease of the kidney.

Three-dimensional biomimetic vascular model reveals a RhoA, Rac1, and N -cadherin balance in mural cell–endothelial cell-regulated barrier function

“…Here, we provide a demonstration in a culture setting that mural cells detach from the endothelium and migrate away from the vessel, and this can occur rapidly during acute exposure to proinflammatory cytokines. The ability to recapitulate this migratory effect in culture, where the concentrations of cytokines are highest at the vessels (versus the interstitial spaces), suggests an active process whereby cytokine stimulation drives mural cells into the matrix and not via a chemoattractant mechanism, as has previously been postulated (56). Given that mural cells dynamically alter their adhesions with the endothelium, this suggests a more active role for mural-endothelial interactions in acute responses than perhaps was previously appreciated.…”

Hyperactive FOXO1 results in lack of tip stalk identity and deficient microvascular regeneration during kidney injury

“…Similar studies in mouse and human kidney disease, however, indicate this is not the case [50, 65, 66]. Although a mild angiogenic response occurs within a few days following acute kidney injury, all models of chronic kidney disease are ultimately characterized by vascular regression without significant vascular regeneration [38, 67].…”

“…Accumulating evidence indicates loss of the kidney microvasculature may be a central or early problem in many forms of kidney disease [55]. Capillary loss leading to ischemia of the nephron, in critical areas of high metabolic demand, are now well documented experimentally [66]. Ischemic tubules of the nephrons respond by releasing inflammatory factors, recruiting leukocytes, exhibiting abnormal salt and water handling, impaired secretion of uremic toxins, setting up the kidney for chronic inflammation, fibrosis and hypertension [55, 68].…”

Kidney Regeneration: Lessons from Development

“…The mechanism of microvascular rarefaction is unclear since there is little evidence of endothelial cell death or proliferative repair after AKI 51, 53 . However, bi-directional signaling between vascular pericytes and endothelium regulates vascular stability, suggesting that capillary rarefaction might result from loss of normal pericytes-endothelial interactions after AKI 54 . Support for this hypothesis comes from a series of studies demonstrating that interference with pericytes-derived signals that stabilize (TIMP3 and EphrinB2) or destabilize (VEGF and ADAMTS1) the microvasculature exacerbates or attenuates respectively, renal fibrosis after AKI 55–57 .…”