Pathogenic Mechanisms of Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a progressive and fatal disease. Sustained pulmonary vasoconstriction and concentric pulmonary vascular remodeling contribute to the elevated pulmonary vascular resistance and pulmonary artery pressure in PAH. Endothelial cells regulate vascular tension by producing endothelium-derived relaxing factors (EDRFs) and endothelium-derived contracting factors (EDCFs). Homeostasis of EDRF and EDCF production has been identified as a marker of the endothelium integrity. Impaired synthesis or release of EDRFs induces persistent vascular contraction and pulmonary artery remodeling, which subsequently leads to the development and progression of PAH. In this review, the authors summarize how EDRFs and EDCFs affect pulmonary vascular homeostasis, with special attention to the recently published novel mechanisms related to endothelial dysfunction in PAH and drugs associated with EDRFs and EDCFs.

It is widely accepted that endothelial dysfunction and apoptosis is critical in the initiation of PAH. EC apoptosis during disease initiation activates a highly proliferating population of pathogenic ECs, which drive PAH progression. 3 Broadly, endothelial dysfunction is considered to be a complex set of biological processes involving EDRF/EDCF imbalance, inflammatory cell adhesion, platelet aggregation, increased oxidative stress and glycolysis, endothelial-tomesenchymal transition, and others. 4 Pulmonary artery smooth muscle cells (PASMCs) and pulmonary artery ECs, as direct participants in pulmonary vascular remodeling, have been the main focus of study in the field of PAH. 5 For PASMCs, proliferation, migration, and media hyperplasia are thought to contribute significantly to pulmonary artery remodeling. 6 For pulmonary artery ECs, endothelial dysfunction is one of the typical vascular alterations in the development of PAH. 7 In this review, we discuss the role of EDRFs and EDCFs in endothelial function during PAH progression.
On the basis of recent findings, we summarize new mechanisms of endothelial dysfunction and novel related targeted drugs in PAH clinical therapy.

ROLE OF EDCFS AND EDRFS IN
PAH PATHOLOGY NITRIC OXIDE. NO, as a vasodilator, is produced by 2 pathways: the classical L-arginine-to-NO pathway and the nonclassical nitrate-nitrite-to-NO pathway. 8 In the classic pathway, the pulmonary vasculature primarily uses NO produced by converting L-arginine through NO synthase. The endothelial NO synthasemediated biosynthesis of NO in ECs is considered to be the main source of bioavailable NO in the pulmonary circulation. 9 Endogenous NO inhibits apoptosis and promotes cell proliferation by promoting the expression of vascular endothelial growth factor, which is essential for angiogenesis in pulmonary vascular development. 10  indicates that L-arginine and tetrahydrobiopurine bioavailability is significantly reduced in pulmonary vascular diseases with endothelial dysfunction. 11,12 The L-arginine antagonists asymmetrical dimethylarginine and symmetrical dimethylarginine were remarkably increased in the plasma and tissues of both rats with pulmonary hypertension and patients with idiopathic PAH. 13 Asymmetrical dimethylarginine inhibits endothelial NO synthase activity through direct binding, which leads to endothelial NO synthase uncoupling and superoxide accumulation. 14 Low tetrahydrobiopurine levels or excess oxidized biopterin (dihydrobiopterin) cause endothelial NO synthase uncoupling and the reduction of oxygen to a superoxide anion. This then scavenges NO and generates other reactive oxygen species, resulting in constrictive and proliferative vascular pathology. 15,16 The progression of PAH is significantly associated with a reduction in endothelial NO synthase expression, which is what may contribute to pulmonary vasoconstriction and media hypertrophy. 17 In PAH, low endothelial NO synthase levels in pulmonary vascular ECs impair NO production, which may lead to increased vascular tone and other cellular activity in the vascular wall. 18  Arachidonic acid is catalyzed by cyclooxygenases and PGI 2 synthetases to produce a series of prostaglandins (PGs). The binding relationship between these ligands and receptors 20 and their functions are shown in

FIGURE 1 Endothelium-Derived Factors and Their Receptors
The regulatory effect of endothelium-derived relaxing factors (EDRFs) and endothelium-derived contracting factors (EDCFs) on vascular tension depends on their specific receptor pathways. 5-HT ¼ 5-hydroxytryptamine; 5HTR ¼ 5-hydroxytryptamine receptor; The signaling pathways of PGs in regulating vascular tone are shown in Figure 2.
In addition to the effects on pulmonary artery ECs PGIS ¼ prostaglandin I synthase; PL ¼ phospholipase; ROS ¼ reactive oxygen species; TxAS ¼ thromboxane synthase; VEGF ¼ vascular endothelial growth factor; other abbreviations as in Figure 1.     Studies have shown that PGI 2 is similar to PGE 2 in its association with pain and inflammation. 78 Peroxisome proliferator-activated receptor a and peroxisome proliferator-activated receptor b/d activation by PGI 2 or its analogs can also maintain endothelial function and vasodilation, likely through endothelial    eventually vascular expansion. 107 The complex interactions of these opposing networks and the imbalance identified in the pathogenesis of PAH highlight the importance of these pathways and the need for further study.

DRUGS RELATED TO EDRFS AND EDCFS FOR PAH TREATMENT
Over the past 20 years, the treatment and manage-    and similar results were also seen in pulmonary hypertension induced by heparin-protamine complexes in goats. 132