Abstract
Hypoxia-inducible factor-1α (HIF-1α) plays a key role in angiogenesis, improves flap survival, and activates autophagy. The effect of HIF-1α-induced autophagy is still debatable. Thus, we investigated the effect of HIF-1α-induced autophagy on multiterritory perforator flap survival. In this study, 99 male Sprague-Dawley rats received multiterritory perforator flap procedure and were divided into three groups with 33 each. The dimethyloxalylglycine (DMOG) plus 3-methyladenine (3-MA) group received intraperitoneal injection of DMOG (40 mg/kg) and 3-MA (10 mg/kg). The DMOG group and control group received comparative DMOG and saline respectively. On postoperative day (POD) 7, HIF-1α’s activities of flap survival and perfusion improvement were confirmed in DMOG group, however, its positive effects were further enhanced by co-administration of autophagy inhibitor, 3-MA. On POD 1, vascular endothelial growth factor, mean microvascular density and blood perfusion were not affected by HIF-1α up-regulation or autophagy inactivation. However, HIF-1α-induced autophagy augments apoptosis and oxidative stress. The increased level of apoptosis and oxidative stress was reversed by 3-MA and resulted in further flap survival improvement. In conclusion, HIF-1α-induced autophagy has a detrimental effect on multiterritory perforator flap survival and the flap survival was determined by the combined effects of ischemia and reperfusion injury.
Highlights
A perforator flap involves a cutaneous perforator artery of 0.5 mm or greater without main vessel[1]
All rats survived without any postoperative infection, and the boundary between survival and necrosis areas was clearly demarcated in each rat on postoperative day (POD) 7 (Fig. 1a)
On POD 1, the differences of both VEGF mRNA and protein expression were not significant among the three groups (Fig. 3a; all P > 0.05), and immunohistochemistry staining showed no significant differences in the mean microvascular density (MVD), among the three groups (Fig. 3b; control: 7.60 ± 0.80, DMOG: 7.67 ± 0.64, DMOG + 3-MA: 7.80 ± 0.53, all P > 0.05). In accordance with these results, the laser Doppler perfusion images showed that the flap perfusion differences were not significant at choke vessel zone (CVZ) on POD 1 (Fig. 3c,d; control: 108.6 ± 1.6, DMOG: 107.7 ± 2.1, DMOG + 3-MA: 108.7 ± 1.6, all P > 0.05). All these results demonstrated that angiogenesis was not affected by Hypoxia-inducible factor-1α (HIF-1α) up-regulation or inhibition of HIF-1α-induced autophagy in the deep circumflex iliac (DCI) artery perforator flap (DCIA-flap) on POD 1
Summary
A perforator flap involves a cutaneous perforator artery of 0.5 mm or greater without main vessel[1] Both clinical and experimental studies demonstrated that necrosis always occurred at the dynamic territory boundary and at the potential territory[2,3,4]. Some authors showed that increased expression of HIF-1α could improve flap survival via vascularization[8,9]. Ischemia/reperfusion injury, overexpression of the autophagy impairs the heart and brain during the period of reperfusion[17,18,19] It still remains unclear whether autophagy is required for flap survival, but our study hypothesized that HIF-1α-induced autophagy may affect multiterritory perforator flap survival according to the effects of autophagy on ischemia/reperfusion injury
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