Obesity Impacts Post‐Myocardial Infarction Neovascularization by Downregulating <scp>AQP1</scp> Expression via the <scp>TRPC5</scp> ‐ <scp>NFATc3</scp> Signaling Pathway

Obesity is associated with impaired angiogenesis and poor recovery following myocardial infarction (MI), yet the underlying molecular mechanisms remain poorly defined. The transient receptor potential cation channel subfamily C member 5 (TRPC5) is known to regulate angiogenesis, but its role in the context of obesity-related MI is unclear. Here, we show that TRPC5 expression is downregulated in obese mice hearts following MI, resulting in compromised angiogenic function. Riluzole, an FDA-approved drug for amyotrophic lateral sclerosis, activates TRPC5 and restores the migration, sprouting, and tube formation function of coronary artery endothelial cells isolated from diet-induced obese (DIO) MI mice. In obese mice, riluzole enhances post-MI neovascularization, reduces infarct size, and improves cardiac function. Notably, TRPC5-mediated angiogenesis requires aquaporin-1 (AQP1), whose expression is regulated by TRPC5 via the nuclear factor of activated T cells 3 (NFATc3) transcription factor. Silencing AQP1 abolishes the pro-angiogenic effects of TRPC5 activation, establishing AQP1 as a critical downstream effector. In conclusion, our data provide evidence that the TRPC5-NFATc3-AQP1 pathway is essential for post-MI angiogenesis in obesity and support riluzole as a promising therapeutic approach to enhance angiogenesis in obese individuals following MI.