Cellular factors
Proliferation of smooth muscular cells in the small peripheral pulmonary arteries is a common characteristic in all forms of PAH. In hypoxic models, fibroblasts of the adventitia migrate to the media and intima, where proliferation and production of matrix proteins are observed [138]. Neovascularization, mainly of the adventitia, occurs concomitantly to the thickening of the vascular walls [139].
In response to certain stimuli, endothelial cells abnormally proliferate to form plexiform lesions in several forms of PAH. Plexiform lesions consist of endothelial cells, matrix proteins and fibroblasts and obliterate the vascular lumen [140]. The stimuli for endothelial proliferation is still unknown but several factors have been incriminated such as hypoxia, inflammation, shear stress, drugs, viral infections and genetic susceptibility. Extrapulmonary cells may also participate in the vascular remodeling responsible for PAH. Indeed, fibrocytes and c-kit + cells are mobilized from the bone marrow, and may differentiate into vascular cells and/or produce pro-angiogenic factors to participate in the pathogenesis of PAH [141,142]. The CXCL12/CXCR4 axis may play an important role in the pulmonary recruitment of these circulating progenitors and can be therapeutically targeted [143].
Inflammatory mechanisms seems to play an important role in certain forms of PAH such as PAH associated with auto immune diseases or HIV infection [144]. In fact, in severe cases of PAH associated with systemic lupus erythematosus disease, some patients improved both clinically and hemodynamically with administrated immunosuppressant treatment. Thirty to 40% of patients with PAH have circulating auto-antibodies and elevated plasma concentrations of pro-inflammatory cytokines such as interleukin 1 (IL-1) and interleukin-6 (IL-6), and chemokines such as fractalkine and MCP-1 [145,146]. Inflammatory cells, such as lymphocytes B and T, macrophages, mastocytes and dendritic cells, can also be found in plexiform lesions of severe PAH [147,148]. Chemokines, like RANTES and fractalkine are also overly expressed in the pulmonary vascular endothelium of PAH patients [145].
Thrombosis and platelet dysfunction can be important in the development of PAH. Abnormalities of thrombosis, endothelial cells or platelets can generate or aggravate thrombosis in situ. Elevated plasma concentrations of D-dimers and fibrinopeptides A and B, in certain patients with PAH, are the proof of an abnormal intravascular coagulation process. Elevated plasma concentrations of von-Willebrand factor and plasminogen activator inhibitor type 1 also reflect endothelial dysfunction in PAH. It has been demonstrated that shear stress creates pro-thrombotic vascular lesions in PAH that may lead to thrombosis in situ. But platelet function is not limited to coagulation. In response to certain stimuli, platelets can produce prothrombotic, vasoactive or mitogenic factors, such as thromboxane A2 (TXA2), platelet-derived growth factor (PDGF), serotonin (5-hydroxytryptamine, 5-HT), transforming growth factor beta (TGF-β) and vascular endothelial growth factor (VEGF) that participate in vasoconstriction and vascular remodeling [149,150].