Capsazepine-mediated TRPV1 blockade impairs angiogenesis by attenuating autophagy in perforator flaps.

Distal necrosis remains a common postoperative complication of perforator flaps, largely due to insufficient perfusion and inadequate angiogenesis in ischemic flap tissue. Transient receptor potential vanilloid type 1 (TRPV1) has been implicated in vascular regulation through calcium-dependent signaling pathways; however, whether pharmacological blockade of TRPV1 affects angiogenesis in perforator flaps remains unclear. In this study, capsazepine was used to pharmacologically block TRPV1 in a rat perforator flap model. The results showed that capsazepine treatment significantly reduced flap survival compared with vehicle treatment (64.5 ± 1.2 % vs. 79.0 ± 1.7 %) and impaired angiogenesis, as indicated by reduced vascular density and decreased expression of VEGF-A, eNOS, and MMP2. Capsazepine also reduced the phosphorylation of CaMKII, CaMKKβ, and AMPK, together with decreased Beclin1 expression, a reduced LC3-II/I ratio, and induced pro-apoptotic changes, as evidenced by increased Bax and cleaved caspase-3 expression and decreased Bcl-2 expression. Notably, pharmacological enhancement of autophagy with rapamycin reduced Bax expression and increased MMP2 expression. Collectively, these findings indicate that capsazepine-mediated TRPV1 blockade impairs perforator flap survival and angiogenesis, at least in part, through reduced CaMKII/CaMKKβ/AMPK activation and attenuation of autophagy. The rapamycin rescue findings position autophagy as an important functional intermediary between TRPV1-associated signaling and the regulation of apoptosis and angiogenesis in perforator flaps.