Smooth muscle cell FTO regulates contractile function.

Area of Science:

• Cardiovascular Biology
• Molecular Genetics
• Vascular Physiology

Background:

• The fat mass and obesity gene (FTO) is an N6-methyladenosine RNA demethylase.
• Genome-wide association studies initially linked FTO to obesity.
• Emerging evidence suggests FTO has mass-independent roles, including in cardiac function.

Purpose of the Study:

• To investigate the role of FTO in smooth muscle cell contractility.
• To determine the effects of smooth muscle-specific FTO deletion on cardiovascular parameters in mice.

Main Methods:

• Generated a conditional and inducible smooth muscle cell-specific Fto knockout mouse model (Myh11 Cre+ Fto).
• Assessed physiological parameters including body mass, metabolism, blood pressure, heart rate, and plasma electrolytes.
• Evaluated mesenteric artery myogenic tone and constriction responses.
• Performed microarray analysis on Fto-/- smooth muscle cells and confirmed findings in human coronary artery cells using FTO siRNA.

Main Results:

• Smooth muscle-specific Fto deletion did not alter body mass or mitochondrial metabolism.
• Mice exhibited significant hypotension, increased heart rate, elevated sodium, and increased plasma renin.
• Mesenteric arteries showed severely impaired myogenic tone and constriction responses.
• Microarray analysis revealed decreased expression of serum response factor (Srf) and its downstream targets (Acta2, Myocd, Tagln) in Fto-deficient smooth muscle cells.

Conclusions:

• FTO is a critical regulator of smooth muscle cell contractility.
• FTO may influence smooth muscle function through the Srf signaling pathway.
• These findings highlight a novel role for FTO in vascular homeostasis beyond its established role in obesity.