Mutations in bone morphogenetic protein receptor ( BMPR2 ) gene have been observed in at least 70% of patients with heritable pulmonary arterial hypertension (HPAH) and in 11-40% with idiopathic PAH (IPAH). However all patients with BMPR2 mutation do not develop PAH, suggesting the need for a second hit. Inflammation, also involved in the pathogenesis of PAH, could play such a role. Our aim was to determine if inflammation, in addition to impaired BMPR2 signaling, could be involved in pulmonary arterial cells dysfunction in PAH. Pre-capillary pulmonary arterial endothelial (EC) and smooth muscle cells (SMC) were isolated from lung parenchyma of transplanted patients with IPAH (n=2) and HPAH with a BMPR2 mutation (n=1). Adhesion capacities of CRP- and TNFα-activated EC to human monocytic cells (U937) were investigated. Mitogenic activity of SMC was evaluated in the presence of CRP or of resting EC. CRP increased adhesion of EC to U937 by 105% (IPAH) and 227% (HPAH). Similarly, TNFα increased adhesion by 249% and 635%. CRP increased mitogenic activity of SMC by 1.4-fold (IPAH) and 2.2-fold (HPAH) vs. control (0.2% FBS). Presence of resting pre-capillary EC increased SMC mitogenic activity by 2.6% (IPAH) and 8.6% (HPAH). These results show that i) pre-capillary pulmonary arterial cells (EC and SMC) isolated from HPAH patient display enhanced adhesion capacities and mitogenic activity in the presence of inflammatory mediators and ii) a potential cross-talk between pre-capillary EC and SMC, suggesting that inflammation may contribute to pulmonary arterial cell dysfunction in PAH.
Vengethasamy et al. (Sun,) studied this question.