Université Côte d'Azur, CNRS, INSERM, IPMC, IHU-RespirERA, Valbonne, France.
Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute, Pittsburgh, PA, USA; Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine and UPMC, Pittsburgh, PA, USA.
Cell Metab. 2024 Jun 4;36(6):1335-1350.e8. doi: 10.1016/j.cmet.2024.04.010. Epub 2024 May 2.
Perivascular collagen deposition by activated fibroblasts promotes vascular stiffening and drives cardiovascular diseases such as pulmonary hypertension (PH). Whether and how vascular fibroblasts rewire their metabolism to sustain collagen biosynthesis remains unknown. Here, we found that inflammation, hypoxia, and mechanical stress converge on activating the transcriptional coactivators YAP and TAZ (WWTR1) in pulmonary arterial adventitial fibroblasts (PAAFs). Consequently, YAP and TAZ drive glutamine and serine catabolism to sustain proline and glycine anabolism and promote collagen biosynthesis. Pharmacologic or dietary intervention on proline and glycine anabolic demand decreases vascular stiffening and improves cardiovascular function in PH rodent models. By identifying the limiting metabolic pathways for vascular collagen biosynthesis, our findings provide guidance for incorporating metabolic and dietary interventions for treating cardiopulmonary vascular disease.
激活的成纤维细胞导致血管周围胶原沉积，从而促进血管僵硬，并引发肺动脉高压（PH）等心血管疾病。然而，血管成纤维细胞是否以及如何重新调整其代谢以维持胶原生物合成尚不清楚。在这里，我们发现炎症、缺氧和机械应激会集中激活肺动静脉外膜成纤维细胞（PAAFs）中的转录共激活因子 YAP 和 TAZ（WWTR1）。结果，YAP 和 TAZ 驱动谷氨酰胺和丝氨酸分解代谢，以维持脯氨酸和甘氨酸的合成代谢，并促进胶原生物合成。在 PH 啮齿动物模型中，对脯氨酸和甘氨酸合成代谢需求的药理学或饮食干预可降低血管僵硬并改善心血管功能。通过确定血管胶原生物合成的限制代谢途径，我们的研究结果为代谢和饮食干预治疗心肺血管疾病提供了指导。
