Pulmonary arterial hypertension (PAH) is defined by elevated pulmonary arterial pressure leading to right ventricular hypertrophy and dysfunction. Significant remodeling of the pulmonary vasculature, including medial hypertrophy and plexiform lesions leads to elevation of pulmonary arterial pressure [1]. The exact mechanism of pulmonary vasculopathy associated with PAH remains unclear [2]. Current PAH treatments target endothelin, nitric oxide, or the prostacyclin pathway [3]. However, incident patients have a 30% risk of death within 3 years [2]. Thus, novel knowledge regarding the molecular mechanism of pulmonary vascular remodeling is desired to develop better treatments against PAH.

There is evidence of increased activity of the renin-angiotensin system (RAS) in PAH patients [4]. However, no clinical data are available to support the efficacy of ACE inhibitors (ACEi) or angiotensin II receptor blockers (ARB) in treatment for PAH [5]. Understanding the alterations in the RAS activity associated with PAH may provide attractive therapeutic targets. In this mini review, we will update the knowledge regarding regulation of the RAS system in PAH compared to primary hypertension. In general, animal models of PAH show up-regulation of classical RAS such as ACE [6,7,8] and angiotensin II type 1 (AT1) receptor [9] as well as suppression of protective angiotensin converting enzyme 2 (ACE2) and angiotensin-(1–7) (Ang1-7) [6, 7, 10]. Table 1 indicates alterations in ACE, ACE2, Ang II and Ang1-7 expression or activity in various animal models of PAH. Mas receptor expression remains unchanged [8, 11]. AT1 receptor (AT1R) expression is increased in a hypoxic model of PAH [9]. There is no consensus on angiotensin II type 2 (AT2) receptor regulation in animal models of PAH [9, 12]. In primary hypertension, similar to PAH the alteration of RAS includes enhancement of classical RAS (ACE [13] and AT1 receptor [14, 15]) and down-regulation of the protective ACE2/Ang1-7 [14, 16, 17]. Regarding AT2 receptor, primary hypertension may upregulate AT2 receptor [18]. Mas receptor expression is unchanged [19]. Figure 1 summarizes overall changes in the RAS in animal models of primary hypertension and PAH.

Table 1 Analysis of ACE, ACE2, AngII and Ang1-7 expression or activity in animal models of PAH
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Fig. 1
figure 1

RAS system dynamics under PAH vs. primary hypertension. Under PAH, increased ACE levels lead to more conversion of Ang I to Ang II [6, 7, 45]. Under PAH, ACE2 levels decrease [6, 7, 10], and Ang1-7 levels decrease [7] or remain unchanged [8, 11]. AT1 receptor (AT1R) expression is increased [9]. However, there is no consensus on AT2R regulation in PAH [9, 12]. Mas receptor (MasR) remains unchanged [8, 11]. Under primary hypertension (Hyp), ACE levels and the conversion of Ang I to Ang II also increase [13]. ACE2 levels decrease [14, 16, 17] and thus Ang1-7 levels decrease [13, 23]. In addition, AT1R expression is enhanced [14, 15]. AT2R may be upregulated [18]. MasR expression remains unchanged [19]

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Several in vivo studies have shown that ACE2 protects against PAH [6, 7, 10, 11]. However, the alteration of RAS in PAH after ACEi or ARB treatment remains unknown. Animals with myxomatous mitral valve disease (MMVD) develop PAH. Dogs with MMVD were treated with ACEi or ARB to evaluate the RAS pathway [20]. Surprisingly, the authors found inhibition of ACE2 activity and the accompanying decline in Ang1-7 by ACEi, which may limit the cardioprotective effect of ACEi in PAH.

ACE2 converts Ang II to Ang1-7, a negative-regulator of the classical RAS [21]. In animal models of primary hypertension, ACEi and ARB either normalizes reduced ACE2 expression or increases it above control levels [13,14,15,16,17, 22,23,24,25]. Table 2 indicates changes in the RAS components in animal models of primary hypertension treated with ACEi or ARB. Up regulation of ACE2 is observed in many of these studies. This upregulation of ACE2 by ACEi/ARB is explained by their inhibitory effects on AT1 receptor. Ang II stimulation of AT1 receptor activates an integrin and metalloproteinase 17 (ADAM17), which cleaves and inactivates ACE2 [26]. Accordingly, plasma ACE2 appears increased in severe cases of cardiovascular diseases [27] as well as hypertension with heart failure in humans [28] potentially through inflammatory activation of ADAM17. However, in female rats with surgical menopause, ACEi led to a downregulation of the cardiac ACE2 expression [23]. In addition, several studies report that ARB upregulates ACE2 mRNA in animal models of hypertension [15, 16, 25]. In contrast, a few studies have shown that ARB does not change ACE2 mRNA abundance in various tissues such as kidney, lung and heart in mice [22, 24]. Accordingly, in animal models of primary hypertension, the effects of ACEi treatment on ACE2 appear inconsistent.

Table 2 Analysis of ACE2, AngII and Ang1-7 expression or activity in animal models of primary hypertension treated with ACEi or ARB
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Regarding ARB effects on the RAS in PAH vs. primary hypertension, it was recently reported that ARB treatment significantly increased the plasma Ang II level in PAH dogs with MMVD [20]. In animal models of primary hypertension, ARB do not usually increase Ang II levels [22, 23, 29, 30]. ARBs may initially cause an increase in renin secretion due to the negative feedback, which could transiently increase Ang II levels. However, this is often counterbalanced by the increased conversion of Ang II to Ang1-7 [31, 32]. For instance, long-term treatment with an ARB, Olmesartan, has been shown to reduce Ang II levels, potentially through increased expression of ACE2 [33]. This modulation can lead to beneficial cardiovascular and renal effects [18].

To better understand the different RAS responses with treatment of ACEi or ARB in PAH vs. primary hypertension, it is important to mention the presence of local/tissue RAS including in the pulmonary system [34]. These local RAS could explain why ACEi and ARB have a different response in PAH compared with primary hypertension. The pulmonary RAS interplay with other pathways potentially contributing to PAH (dysregulation of the NO and prostacyclin pathways and activation of the endothelin pathway) might also explain the differences between systemic and pulmonary hypertension. The interaction between Ang1-7, NO and the endothelin pathway and its therapeutic implication has been demonstrated in hypoxia-induced animal model of pulmonary hypertension [35].

There are several reports testing the overexpression or administration of ACE2 in animal models of primary hypertension [36,37,38,39]. In Ang II-induced hypertension, transgenic rats expressing ACE2 in vascular smooth muscle cells significantly increased circulating levels of Ang1-7. Thus, the vasoconstrictive response to Ang II was weakened, resulting in a decrease in arterial blood pressure [38]. In addition, treatment with mouse recombinant ACE2 resulted in a significant increase in the conversion of Ang II to Ang1-7 [39].

In patients with PAH, systemic and pulmonary Ang II levels have been reported to be elevated [34], while serum ACE2 levels were decreased [40]. These clinical data suggest that in patients with PAH, administration of exogenous ACE2 may be a potential treatment.

Compared to normotensive individuals, in patients with primary hypertension, serum ACE2 concentrations were higher and significantly associated with left ventricular hypertrophy [41]. This contradictory increase in ACE2 seems to be compensatory to high blood pressure [21]. However, in one study treatment with ARB did not alter ACE2 levels in serum [42]. In addition, ACEi treatment in primary hypertension did not alter serum ACE2 levels [42, 43]. These results indicate variability in the impact of ACEi/ARB on ACE2 expression across different hypertensive populations.

In conclusion, the dynamics of RAS under ACEi or ARB administration appear to differ between PAH and primary hypertension. Although RAS activation is common to both PAH and primary hypertension, the effects of ACEi or ARB depend on the given context, which highlights the complexity of the RAS system regulation in cardiovascular disease. In PAH, ACEi may inhibit ACE2 activity and reduce Ang1-7. Thus, supplementing ACEi with ACE2 or Ang1-7 is an attractive treatment against PAH. Of note, it has been recently reported that significant numbers of PAH patients have primary hypertension [44]. Accordingly, further research is desired to explore the treatment of these populations with ACEi or ARB.