Molecular factors
Many authors consider pulmonary vasoconstriction as an early event in the process of PAH. Vasoconstriction has been associated with an abnormal function or expression of potassium channels and with endothelial dysfunction [107]. Endothelial dysfunction results in a decreased production of vasodilators such as nitric oxide (NO) and prostacyclin and an increased production of vasoconstrictors such as endothelin-1 [153].
Prostacyclin (prostaglandin I2) is a potent pulmonary vasodilator that acts via the cyclic adenosine monophosphate (cAMP) pathway. It inhibits the proliferation of smooth muscle cells and decreases platelet aggregation. Production of prostacyclin is reduced in endothelial cells of patients with PAH [154]. PAH therapy based on prostacyclin and its derivates have proven efficacy both hemodynamically and in clinical trials. NO is also a pulmonary vasodilator which acts via the cyclic guanosine monophosphate (cGMP) pathway. To increase pulmonary vasodilatation dependant on NO, a recent therapeutic strategy has targeted type 5 phosphodiesterase which degrades cGMP. Sildenafil or tadalafil, type 5 phosphodiesterase inhibitors, have proven their efficacy in patients with PAH [155]. Vasoactive intestinal peptide (VIP) is a neurotransmitter that has systemic and pulmonary vasodilator properties. It also inhibits smooth cell proliferation and decreases platelet aggregation and acts via the activation of the cAMP and cGMP systems [156]. Low plasmatic concentrations of VIP have been measured in pulmonary arteries of patients with PAH.
Endothelin-1 (ET-1) is an endothelially-derived peptide that has two receptor subtypes, designated as endothelin A (ETRA) and endothelin B (ETB), located on smooth muscle cells of pulmonary arteries. By ligating the ETRA, ET-1 intracellular calcium concentrations increase and activates the protein kinase C pathway [157]. ET-1 is a potent pulmonary vasoconstrictor and stimulates mitosis of arterial smooth muscle cells, thus contributing to pulmonary vascular remodeling. Pulmonary and plasma levels of ET-1 are elevated in human PAH and in experimental animal models of PAH [158]. The therapeutic efficacy of endothelin receptor antagonists (Ambrisentan, Bosentan) has been demonstrated in clinical trials in the pathophysiology of PAH.
In hypoxic models of PAH, hypoxia inhibits one or several voltage dependant potassium channels of the pulmonary arterial smooth muscle cells. This leads to membrane depolarization and opening of voltage dependant calcium channels with a subsequent increase of the intracellular calcium concentration and cellular contraction. Certain potassium channels are under expressed in pulmonary artery smooth muscle cells of patients with PAH [159,160]. It is still unknown whether abnormalities of the potassium channels are acquired or genetic. However, it has been demonstrated that anorexigens, such as dexfenfluramine and aminorex, directly inhibit certain potassium channel subtypes [161]. Certain medications such as dichloroacetate and sildenafil increase the expression and function of potassium channels.
In PAH, plasmatic concentrations of serotonin (5-hydroxytryptamine, 5-HT) are elevated [150]. An association between anorexigens and serotonin was established in the 1960s. Aminorex and fenfluramin both increase plasmatic levels of serotonin. The variability of the expression and activity of the transporter of 5-HT (5-HTT) contributes to pulmonary vascular remodeling in human and experimental models of PAH [162]. Some studies have shown that the serotonin selective reuptake inhibitor fluoxetin prevents the development of PAH in mice [163]. Some 5-HT receptor subtypes may also be implicated in the development of hypoxia induced PAH [164].
Rho proteins regulate fundamental cellular functions such as contraction, migration, proliferation and apoptosis. Several studies have implicated Rho protein A and Rho kinases in the vasoconstriction and vascular remodeling of PAH [165,166]. RhoA and Rho kinase activities are increased in idiopathic PAH, in association with enhanced RhoA serotonylation. Direct involvement of the 5-HTT/RhoA/Rho kinase signaling pathway in 5-HTT-mediated pulmonary artery-smooth muscle cell (PA-SMC) proliferation and platelet activation during PH progression identify RhoA/Rho kinase signaling as a promising target for new treatments against PH [167].
Hypoxia inducible factor-1 (HIF-1) is a transcription factor that principally regulates cellular adaptation to hypoxia but also regulates several genes implicated in angiogenesis, erythropoiesis, cellular metabolism and survival [168]. In experimental mice heterozygote for the gene coding for HIF-1 alpha, hypoxia induced right ventricular hypertrophy, right ventricular pressure and medial thickening of pulmonary arterioles are reduced [169]. In immunohistological analysis of human plexiform lesions of patients with severe PAH, there was an overexpression of HIF-1 alpha in proliferating endothelial cells [170].
In conclusion, the pathophysiology of PAH is heterogeneous and multifactorial. The genetic mutations found in familial PAH and in a proportion of sporadic PAH are neither necessary nor sufficient for the development of PAH. Therefore, the current hypothesis is that of a genetic predisposition for PAH followed by a superimposed environmental factor (infection, inflammation, autoimmunity). Our understanding of the underlying pathophysiological mechanisms of PAH has lead to the development of new treatments such as prostacyclin analogues, endothelin receptor antagonists and type 5 phosphodiesterase inhibitors. However, future progress is still necessary in order to discover new pathophysiological pathways and to develop new therapeutic strategies in PAH.