Adipsin alleviates cold exposure-induced coronary microvascular dysfunction through a Gα13-dependent mechanism

BACKGROUND: Cold exposure is a well-recognized environmental risk factor that contributes to coronary microvascular dysfunction. Adipsin, an adipokine with known cardioprotective properties, has not been fully explored in the context of cold exposure-induced cardiovascular injury. This study aimed to elucidate the role of Adipsin in modulating coronary microvascular function under cold stress and to investigate the underlying mechanisms. METHODS: Adipose tissue-specific Adipsin transgenic mice (Adipsin-Tg) and wild-type controls were exposed to cold conditions (4 °C) for four weeks. Cardiac function, perivascular fibrosis, and coronary microvascular function were assessed. Serum Adipsin levels were selectively reduced by injecting AAV9-shRab27a into inguinal white adipose tissue (ingWAT). Exosomes derived from the ingWAT of Adipsin-Tg mice were isolated and tested for their effects on endothelial barrier function under cold stress. Mechanistic studies focused on the RhoA/Rock1 signaling pathway, cytoskeletal remodeling, and adherens junctions (AJs) stability in cardiac microvascular endothelial cells (CMECs). RESULTS: Cold exposure significantly reduced Adipsin expression in ingWAT, accompanied by impaired cardiac diastolic function, increased perivascular fibrosis, and disrupted coronary microvasculature. Overexpression of Adipsin in adipose tissue alleviated these pathological changes, whereas knockdown of serum Adipsin via AAV9-shRab27a reversed the protective effects. Exosomes enriched with Adipsin restored endothelial barrier integrity and improved microvascular function under cold stress. Mechanistically, Adipsin-enriched exosomes inhibited the RhoA/Rock1 pathway and MLC phosphorylation, preserved cytoskeletal architecture, and stabilized AJs by preventing VE-cadherin phosphorylation and internalization. Gα13 was identified as a downstream mediator of Adipsin, and its deficiency abolished the inhibitory effects of Adipsin on RhoA/Rock1 signaling. CONCLUSION: Adipsin plays a protective role against cold stress-induced coronary microvascular dysfunction and cardiac diastolic dysfunction by modulating Gα13-dependent inhibition of the RhoA/Rock1 pathway. These findings support the therapeutic potential of Adipsin in preventing cold exposure-related cardiovascular injury.