Right ventricular (RV) function is the predominant determinant of survival in patients with pulmonary arterial hypertension (PAH). In preclinical models, pharmacological activation of BMP (bone morphogenetic protein) signaling with FK506 (tacrolimus) improved RV function by decreasing RV afterload. FK506 therapy further stabilized three patients with end-stage PAH. Whether FK506 has direct effects on the pressure-overloaded right ventricle is yet unknown. We hypothesized that increasing cardiac BMP signaling with FK506 improves RV structure and function in a model of fixed RV afterload after pulmonary artery banding (PAB). Direct cardiac effects of FK506 on the microvasculature and RV fibrosis were studied after surgical PAB in wild-type and heterozygous Bmpr2 mutant mice. RV function and strain were assessed longitudinally via cardiac magnetic resonance imaging during continuous FK506 infusion. Genetic lineage tracing of endothelial cells (ECs) was performed to assess the contribution of ECs to fibrosis. Molecular mechanistic studies were performed in human cardiac fibroblasts and ECs. In mice, low BMP signaling in the right ventricle exaggerated PAB-induced RV fibrosis. FK506 therapy restored cardiac BMP signaling, reduced RV fibrosis in a BMP-dependent manner independent from its immunosuppressive effect, preserved RV capillarization, and improved RV function and strain over the time course of disease. Endothelial mesenchymal transition was a rare event and did not significantly contribute to cardiac fibrosis after PAB. Mechanistically, FK506 required ALK1 in human cardiac fibroblasts as a BMPR2 co-receptor to reduce TGFβ1-induced proliferation and collagen production. Our study demonstrates that increasing cardiac BMP signaling with FK506 improves RV structure and function independent from its previously described beneficial effects on pulmonary vascular remodeling.

右心室 (RV) 功能是肺动脉高压 (PAH) 患者生存的主要决定因素。在临床前模型中，使用 FK506（他克莫司）对 BMP（骨形态发生蛋白）信号传导的药理学激活通过降低 RV 后负荷来改善 RV 功能。FK506 治疗进一步稳定了三名终末期 PAH 患者。FK506 是否对压力超负荷的右心室有直接影响尚不清楚。我们假设在肺动脉束带 (PAB) 后固定 RV 后负荷模型中，用 FK506 增加心脏 BMP 信号可以改善 RV 结构和功能。在野生型和杂合Bmpr2手术 PAB 后研究了 FK506 对微血管和 RV 纤维化的直接心脏影响突变小鼠。在连续 FK506 输注期间，通过心脏磁共振成像纵向评估 RV 功能和应变。进行内皮细胞 (ECs) 的遗传谱系追踪以评估 ECs 对纤维化的贡献。在人类心脏成纤维细胞和 EC 中进行了分子机制研究。在小鼠中，右心室中的低 BMP 信号放大了 PAB 诱导的 RV 纤维化。FK506 治疗恢复了心脏 BMP 信号，以 BMP 依赖性方式减少了 RV 纤维化，独立于其免疫抑制作用，保留了 RV 毛细血管化，并随着疾病的时间进程改善了 RV 功能和应变。内皮间质转化是一种罕见的事件，在 PAB 后对心脏纤维化没有显着影响。机械地，FK506 需要人心脏成纤维细胞中的 ALK1 作为 BMPR2 共受体来减少 TGFβ1 诱导的增殖和胶原蛋白的产生。我们的研究表明，用 FK506 增加心脏 BMP 信号可以改善 RV 结构和功能，而与之前描述的对肺血管重塑的有益作用无关。