Role of Pericytes in Fibrosis

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It is becoming increasingly clear that microvascular pericytes contribute to the pathogenesis of fibrosis in a number of diverse tissues by both direct and indirect mechanisms. Microvascular pericytes have been proposed as mesenchymal precursor cells, and it has been argued that pericytes play a direct role in the pathophysiology of fibrosis by their transdifferentiation into collagen-synthesizing cells. Evidence from morphological studies has shown that during angiogenesis, pericytes migrate from the microvascular wall into the interstitium and acquire a fibroblast-like morphology. In hypertrophic scars and SSc skin, collagen-synthesizing cells are predominantly located adjacent to microvessels. More recently, studies have shown that in a number of diverse dermal conditions associated with increased synthesis of extracellular matrix such as SSc, wound healing, and excessive dermal scarring, pericytes have been found to have a common activated phenotype. Specifically they express PDGF-b receptors and the high-molecular-weight melanoma-associated antigen (HMW-MAA), a known activation marker [5, 6]. Concurrent in vitro studies showed that explanted pericytes with the same activated phenotype underwent a spontaneous transdifferentiation to collagen-synthesizing fibroblasts. A similar phenomenon has also been identified in the development of liver fibrosis where liver pericytes or Ito cells are the principal collagen-producing cells in the fibrotic lesion. Central to this fibrogenic potential is a phenotypic transdifferentiation from liver pericyte to an activated myfibroblastic stellate cell. Like pericytes, myofibroblasts express a-SMA and share phenotypic traits of both fibroblasts and smooth muscle cells. Myofibroblasts were initially described in wound healing where their principal function is the contraction of the provisional granulation tissue prior to their removal by apoptosis. They have subsequently been identified in a number of different conditions associated with fibrosis and scarring, and it has been postulated that a failure in the clearance of myofibroblasts may be important in distinguishing an acute wound response from a chronic fibrotic disorder. Therefore, targeted prevention of a pericyte to myofibroblast transdifferentiation may be of therapeutic value in fibrosis.

Pericytes can also modulate the activity and function of other cells involved in the fibrotic response. In wound healing and SSc, fibrosis is preceded by an infiltration of inflammatory mononuclear cells. Recently knockout mouse models have shown that pericytes play a key role in determining transendothelial cell permeability. Furthermore, liver pericytes are known to express adhesion molecules during liver injury and modulate the recruitment and migration of mononuclear cells within the perisinusoidal space of diseased livers. Pericytes are also able to synthesize a number of growth factors, notably TGF-b, connective tissue growth factor, and ET-1, all of which have been established as potent profibrotic modulators of fibroblast function.

Perhaps a key pathway in the pathological activation of microvascular pericytes during fibrosis is the PDGF-BB/p receptor pathway. In normal tissue, PDGF-b receptors are not constitutively expressed; however, in a number of diverse fibrotic conditions in skin, lung, and kidney, peri-cytes have been shown to overexpress PDGF-P receptors. The PDGF-BB/p receptor axis is a key developmental pathway, central to the recruitment of pericytes to developing vessels. Whereas PDGF-BB has been shown to induce both pericyte proliferation and migration in vitro, its role in vivo is currently less well understood.

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