Endothelial effects of atrial natriuretic peptide (ANP) prevent pulmonary arterial remodelling and hypertension

肺动脉高压（PAH）是一种罕见但致命的肺部疾病的不同来源。内皮细胞功能障碍与特发性和家族性PAH的发病机制有关，但具体机制尚不清楚。预防环GMP（cGMP）降解（西地那非）或刺激cGMP产生（一氧化氮/NO调节的鸟苷酸环化酶的激活剂）的药物的有益作用表明受损的血管cGMP信号传导关键地参与肺血管重塑和收缩的发展。除NO外，心房肽（ANP）和B型利钠肽（BNP）通过其共享的鸟苷酸环化酶A（GC-A）受体刺激所有类型的肺血管细胞（即内皮细胞（EC）、平滑肌细胞（SMC）和成纤维细胞）中cGMP的产生。值得注意的是，我们的研究表明，具有GC-A受体的整体或条件性EC限制性缺失的小鼠在静息条件下已经发展出显著的PAH，伴随右心室（RV）收缩压增加、RV肥大、小肺动脉的肌化增强和肺小动脉稀疏。相比之下，SMC特异性消融GC-A不会引起肺改变。因此，GC-A在EC中的表达和功能对于防止肺血管重构和PAH至关重要。在这里，我们提出了EC GC-A KO和对照小鼠的分子和功能研究，以剖析内皮ANP/GC-A/cGMP通路对肺EC增殖/活力和EC与SMC或炎症细胞之间的旁分泌串扰的影响。这些体内/离体研究将与对培养的人和小鼠肺EC和SMC的研究相补充，以进一步了解PAH的原因和发病机制，即内皮利钠肽信号传导的作用。

Pulmonary arterial hypertension (PAH) is a rare but fatal lung disease of diverse origins. Endothelial cell dysfunction is (co)causally involved in the pathogenesis of idiopathic and familial PAH, but the specific mechanisms are unclear. The beneficial effect of drugs preventing cyclic GMP (cGMP) degradation (sildenafil) or stimulating cGMP production (activators of the nitric oxide/NO- regulated guanylyl cyclase) suggests that impaired vascular cGMP signaling is critically involved in the development of pulmonary vascular remodelling and constriction. Besides NO, atrial (ANP) and B-type natriuretic peptides (BNP), via their shared guanylyl cyclase A (GC-A) receptor, stimulate cGMP production in all types of pulmonary vascular cells (i.e. endothelia (EC), smooth muscle cells (SMC) and fibroblasts). Notably, our studies showed that mice with either global or conditional, EC-restricted deletion of the GC-A receptor develop marked PAH already under resting conditions, with increased right ventricular (RV) systolic pressure, RV hypertrophy, enhanced muscularization of small pulmonary arteries and pulmonary arteriolar rarefaction. In contrast, SMC-specific ablation of GC-A did not provoke pulmonary alterations. Thus, expression and function of GC-A in ECs is critical to prevent pulmonary vascular remodelling and PAH. Here we propose molecular and functional studies in EC GC-A KO and control mice to dissect the effects of the endothelial ANP/GC-A/cGMP pathway on pulmonary EC proliferation/viability and on the paracrine crosstalk between EC and SMC or inflammatory cells. These in vivo/ex vivo studies will be complemented with studies on cultured human and murine pulmonary EC and SMC, to further our understanding of the cause and pathogenesis of PAH, i.e. the role of endothelial natriuretic peptide signaling.