Mild-to-moderate pulmonary hypertension (PH) is a common complication of chronic obstructive pulmonary disease (COPD). As another well-known and extensively researched prostaglandins, prostaglandin E2 (PGE2) and its downstream signaling have been found to play an important role in various biological processes. Emerging evidence has revealed that PGE2 and its receptors (i.e., EP1–4) are involved in the regulation of pulmonary vascular homeostasis and remodeling.
PGI2 analogues |
IP |
EP1 |
EP2 |
EP3 |
EP4 |
|
Iloprost |
Human |
4 |
1 |
1172 |
203 |
212 |
Mouse |
11 |
21 |
1600 |
27 |
2300 |
|
Treprostinil |
Human |
32 |
212 |
3.6 |
2505 |
826 |
Mouse |
YES |
ND |
YES |
ND |
ND |
|
Beraprost |
Human |
39 |
680 |
|||
Mouse |
16 |
110 |
||||
Cicaprost |
Human |
17 |
>1340 |
>1340 |
255 |
44 |
Mouse |
10 |
1300 |
170 |
It has been reported that oral administration of EP1 antagonist SC51322 reduces the blood pressure of spontaneously hypertensive rats. In addition, the systolic blood pressure of EP1 gene knockout mice was significantly lower than that of wild type mice, indicating that EP1 has the effects of constricting blood vessels and increasing blood pressure [7]. In a severe hypertension model, EP1 knockout was able to reduce blood pressure and alleviate organ damage [8]. In the pulmonary vein, EP1 counteracts the relaxation induced by PGs [9]. The selectivity of iloprost to different receptors is poor, and its effect of activating IP and EP1 is basically the same [10]. Iloprost has poor clinical efficacy, as it targets EP1 as well [11]. The EP1 antagonist SC-19220 inhibits the endocannabinoid arachidonyl ethanolamide (anandamide)-induced increase in pulmonary artery pressure [12]. Studies have shown that PDGF and VEGF promote abnormal proliferation and migration of ECs and SMCs to promote vascular remodeling, which can be reversed by the tyrosine kinase inhibitor imatinib in a dose-dependent manner [13]. Blockade of EP1/3 and TP or inhibition of the MAP2K, p38MAPK, PI3K-α/γ, and AKT/PKB signaling pathways prevented PDGFinduced contraction [14]. Due to the high contribution of the pulmonary venous bed to pulmonary vascular resistance, PDGF-BB-induced contraction is enhanced in the varicose veins of the pulmonary venous system [15]. Immunohistochemistry has shown that EP1 is mainly expressed in human pulmonary veins [16][86]. However, in PH patients and hypoxiainduced PH mice, EP1 expression did not change significantly [17]. Currently, the effect of EP1 on PH has not been reported.
The expression of EP2 in PASMCs is upregulated in patients with PH [18][88]. Treprostinil, a drug currently used to treat PH, has high affinity for EP2 and IP [4][74] and increases cAMP content by activating EP2 in macrophages [19][23]. It is the only PGI2 analogue that can effectively bind to EP2, and the EP2 antagonist PF-04418948 (1 μM) significantly reduced the anti-proliferative effect of treprostinil [18][88]. In addition, studies have found that EP2 is associated with increased proliferation and migration of SMCs, all of which suggests that EP2 receptors have a protective role in vascular remodeling [20][21][89,90]. Treprostinil can significantly reduce the recruitment of fibroblasts at the site of vascular remodeling in hypoxic PH, and fibroblasts play a role in the inflammatory and proliferative phase of blood vessels [22][91]. Interestingly, EP2 expression in PASMCs was not affected in an MCT-induced rat PH model [23][92]. At present, the effect of EP2 on PH needs to be further explored.
EP3 is widely expressed in the whole-body tissues of mice [24][93]. EP3 agonists have a strong contractile effect on isolated human pulmonary arteries [25][94]. The mean arterial pressure of EP3 knockout mice was found to be lower than that of wild type mice, suggesting that EP3 has the functions of constricting blood vessels and increasing blood pressure [26][95]. As the first stable oral PGI2 analogue, beraprost is mainly used in the clinical treatment of PH, arterial occlusive diseases, peripheral vascular diseases, renal failure, etc. [27][96]. Beraprost has been shown to improve exercise capacity and hemodynamics, thereby alleviating PH symptoms [28][97]. Other results have demonstrated that in addition to binding to IP, beraprost has a strong binding affinity with EP3 (Ki 110 Nm) in rats [19][23]. Many studies have provided evidence that the contractile effects of PGI2 analogues are mediated through EP3 receptors [5][29][30][75,98,99]. In patients with PH who were treated with beraprost but not selexipag (a prostaglandin receptor selective agonist), the vasodilator efficacy was reduced by the constriction caused by activation of EP3 in the pulmonary artery. In addition, a common side effect of beraprost is paradoxical constriction of the femoral artery due to activation of EP3 receptor. Therefore, patients with PH treated with PGI2 analogues experience leg pain, whereas selexipag is less likely to cause this side effect [31][100]. Esuberaprost, an isoform of beraprost, is five times more potent than beraprost in vasodilation of rat pulmonary arteries. Esuberaprost promotes cAMP production and inhibits proliferation of human PASMCs with inhibitory effects 40 times more potent than beraprost (EC50 3 nM and EC50 120 nM). The EP3 antagonist L-798106 can significantly reduce the pulmonary artery constriction effect of high concentrations of Esuberaprost. It is important to understand the role of EP3 in the contractile response, as this could limit the dose of PGI2 analogues provided therapeutically and potentially give rise to unwanted side effects [32][101]. In addition, EP3 plays a role in pulmonary vascular remodeling. Overexpression of EP3, especially its α and β isoforms, promotes the proliferation and migration of vascular SMCs, and EP3 knockout significantly improves vascular remodeling caused by a femoral artery guidewire strain [33][102]. Furthermore, EP3 expression has been found to be upregulated in hypoxia-treated PASMCs. The EP3 antagonist L-798106 ameliorated MCT- and hypoxia-induced PH and inhibited ECM deposition in pulmonary arteries. EP3 (mainly EP3α and EP3β) knockout in SMCs alleviated PH by inhibiting Rho/TGF-β1 signaling [17][87]. However, EP3-deficient mice have increased bleeding tendency [34][103]. Distal human PASMCs isolated from the pulmonary arteries (outer diameter: 1 mm) were found to be more susceptible to PGI2 analogue-induced proliferation inhibition than PASMCs isolated from the proximal pulmonary arteries (outer diameter: 0.8 mm) [35][104]. The expression of IP, EP3, FP, and TP in MCT-treated rats were all decreased compared with control rats (p < 0.05 or p < 0.01) [35][104]. Thus, EP3 is involved in the occurrence of PH, and its antagonists have therapeutic potential.