Evidence of Dysfunction of Endothelial Progenitors in Pulmonary Arterial Hypertension

Abstract

Rationale: Severe pulmonary arterial hypertension (PAH) is characterized by the formation of plexiform lesions and concentric intimal fibrosis in small pulmonary arteries. The origin of cells contributing to these vascular lesions is uncertain. Endogenous endothelial progenitor cells are potential contributors to this process. Objectives: To determine whether progenitors are involved in the pathobiology of PAH. Methods: We performed immunohistochemistry to determine the expression of progenitor cell markers (CD133 and c-Kit) and the major homing signal pathway stromal cell-derived factor-1 and its chemokine receptor (CXCR4) in lung tissue from patients with idiopathic PAH, familial PAH, and PAH associated with congenital heart disease. Two separate flow cytometric methods were employed to determine peripheral blood circulating numbers of angiogenic progenitors. Late-outgrowth progenitor cells were expanded ex vivo from the peripheral blood of patients with mutations in the gene encoding bone morphogenetic protein receptor type II (BMPRII), and functional assays of migration, proliferation, and angiogenesis were undertaken. Measurements and Main Results: There was a striking up-regulation of progenitor cell markers in remodeled arteries from all patients with PAH, specifically in plexiform lesions. These lesions also displayed increased stromal cell-derived factor-1 expression. Circulating angiogenic progenitor numbers in patients with PAH were increased compared with control subjects and functional studies of lateoutgrowth progenitor cells from patients with PAH with BMPRII mutations revealed a hyperproliferative phenotype with impaired ability to form vascular networks. Conclusions: These findings provide evidence of the involvement of progenitor cells in the vascular remodeling associated with PAH. Dysfunction of circulating progenitors in PAH may contribute to this process. Keywords: pulmonary hypertension; endothelial progenitorSevere pulmonary arterial hypertension (PAH) is a rare but devastating condition with a poor prognosis. The conventional model of pulmonary endothelial dysfunction in PAH includes endothelial cell damage, failure of repair, and compromise of barrier integrity (1). Two types of vascular lesions predominate in small pulmonary arteries: concentric intimal lesions consisting of myofibroblast proliferation and smooth muscle hypertrophy with resultant luminal narrowing, and plexiform lesions characterized by disorganized focal proliferation of endothelial channels (2). The vascular injury has been hypothesized to lead to the emergence of apoptosis-resistant endothelial cell clones, and Lee and coworkers (3) have suggested that plexiform lesions, at least in the idiopathic form of PAH, are monoclonal in origin. The appearance of plexiform lesions is thought to signify a poor prognosis (4), but little is understood about the evolution of these focal areas of neoangiogenesis. Their contribution to increased vascular resistance is unclear, although three-dimensional reconstruction studies sugge...

Involvement of endothelial progenitor cells in the formation of plexiform lesions in broiler chickens: possible role of local immune/inflammatory response

“…). This finding from our avian model provides the first supportive evidence for the claim that EPCs contribute to the formation of PLs in the human (Toshner et al, 2009). Interestingly, in mature PLs with glomeruloidlike appearance, the foam-like macrophages also expressed both CD133 and VEGFR-2.…”

“…Increasing evidence suggests that these cells play a fundamental role in tissue regeneration and vascular repair both by differentiating into mature endothelial cells and by secretion of proangiogenic mediators (George et al, 2011;Zhang et al, 2013). Interestingly, it has been found that PAH patients had increased EPCs (CD133 + ) in remodeled pulmonary arteries, specifically in PLs, leading to the suggestion that the formation of PLs is associated with EPC dysfunction (Toshner et al, 2009). However, the mechanisms underlying EPC dysfunction during the development of PLs remain poorly understood.…”

HIF2α–arginase axis is essential for the development of pulmonary hypertension

“…BOEC isolation culture. BOECs have been extensively used as a model for studying in vitro endothelial function in vascular disorders (29,30) and we have previously demonstrated their close functional and gene expression similarity to pulmonary artery endothelial cells (31). BOECs were isolated as previously described (44).…”

“…Blood outgrowth endothelial cells (BOECs) have been extensively used as a model for studying in vitro endothelial function in vascular disorders (29,30) with close functional and gene expression similarity to pulmonary artery endothelial cells (31). Previous work has shown enhanced expression and activity of Arg-2 in PAH patients (27,32).…”

Modulation of Intersectin-1s Lung Expression Induces Obliterative Remodeling and Severe Plexiform Arteriopathy in the Murine Pulmonary Vascular Bed

“…Thus, a major finding of our study is that in our murine model, the various degrees of concentric intimal thickening, the muscularization of arteriolar wall, and development of the plexogenic lesions were triggered by a granzyme B proteolytic cleavage fragment of ITSN, further supporting the idea of inflammation as a promoting mechanism that contributes to pulmonary vascular remodeling in PAH. Whether plexiform lesions are a morphological consequence of inflammation, of high blood pressure as in the SU5416/hypoxia/normoxia rat model, 18 or of BMPR2 mutations, 40 it seems that formation of plexiform lesions is a multifactorial process and when they form, they contribute to and sustain the remodeling of the pulmonary vasculature and PAH progression.…”