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P ulmonary arterial hypertension (PAH) is a rapidly progressive disease characterized by obstructive remodeling of distal pulmonary arteries (<500 μm), leading to a progressive elevation in pulmonary vascular resistance and subsequent right heart failure and death. There is currently no cure for PAH, which has a very poor prognosis (mean survival of 2.8 years).1 It is well known that pulmonary arteries display complex structural and functional changes in PAH and that pulmonary endothelial cell (EC) dysfunction plays a crucial role in the disease progression. Despite an increased knowledge in the past years about PAH pathobiological cellular and molecular mechanisms, we still do not know what initiates this disease and its characteristic pulmonary vascular remodeling. Editorial see p 1545 Clinical Perspective on p 1597Pericytes are central regulators of vascular development, stabilization, maturation, and remodeling, modulating EC Background-Pericytes and their crosstalk with endothelial cells are critical for the development of a functional microvasculature and vascular remodeling. It is also known that pulmonary endothelial dysfunction is intertwined with the initiation and progression of pulmonary arterial hypertension (PAH). We hypothesized that pulmonary endothelial dysfunction, characterized by abnormal fibroblast growth factor-2 and interleukin-6 signaling, leads to abnormal microvascular pericyte coverage causing pulmonary arterial medial thickening. Methods and Results-In human lung tissues, numbers of pericytes are substantially increased (up to 2-fold) in distal PAH pulmonary arteries compared with controls. Interestingly, human pulmonary pericytes exhibit, in vitro, an accentuated proliferative and migratory response to conditioned media from human idiopathic PAH endothelial cells compared with conditioned media from control cells. Importantly, by using an anti-fibroblast growth factor-2 neutralizing antibody, we attenuated these proliferative and migratory responses, whereas by using an anti-interleukin-6 neutralizing antibody, we decreased the migratory response without affecting the proliferative response. Furthermore, in our murine retinal angiogenesis model, both fibroblast growth factor-2 and interleukin-6 administration increased pericyte coverage. Finally, using idiopathic PAH human and NG2DsRedBAC mouse lung tissues, we demonstrated that this increased pericyte coverage contributes to pulmonary vascular remodeling as a source of smooth muscle-like cells. Furthermore, we found that transforming growth factor-β, in contrast to fibroblast growth factor-2 and interleukin-6, promotes human pulmonary pericyte differentiation into contractile smooth muscle-like cells. Conclusions-To the best of our knowledge, this is the first report of excessive pericyte coverage in distal pulmonary arteries in human PAH. We also show that this phenomenon is directly linked with pulmonary endothelial dysfunction. 10 In particular, pericytes that are found along arterioles and capillaries express different degrees...

We report here that CD74 and MIF are markedly increased and activated in patients with iPAH, contributing to the abnormal proinflammatory phenotype of pulmonary ECs in iPAH.