Dietary intake and glutamine-serine metabolism control pathologic vascular stiffness

• DOI: 10.1016/j.cmet.2024.04.010
• Publication Date: 2024-05-02T14:35:52Z
• Authors: Nesrine S. Rachedi; Ying Tang; Yi-Yin Tai; Jingsi Zhao; Caroline Chauvet; Julien Grynblat; Kouamé Kan Firmin...; Leonard Estephan; Stéphanie Torrino; Chaima Sbai; Amel Ait-Mouffok; Joseph D. Latoche; Yassmin Al Aaraj; Frederic Brau; Sophie Abélanet; Stephan Clavel; Yingze Zhang; Christelle Guille...; Naveen V.G. Kumar; Sina Tavakoli; Olaf Mercier; Michael G. Risbano; Zhong-Ke Yao; Guangli Yang; Ouathek Ouerfelli; Jason S. Lewis; David Montani; Marc Humbert; Matthew L. Steinh...; Carolyn J. Anderson; William M. Oldham; Frédéric Perros; Thomas Bertero; Stephen Y. Chan
• Keywords: Male; Mice, Inbred C57BL; Mice; Vascular Stiffness; Glutamine; Hypertension, Pulmonary; Serine; Animals; Humans; Collagen; Fibroblasts; Rats

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.