Connexin 40 is necessary for recovery of ischemic hindlimb perfusion ‐ inflammation and gender considerations

Abstract

Recovery of tissue perfusion in the ischemic hindlimb is reduced, inflammatory response increased, and survival of distal limb tissue compromised in Cx40‐deficient (40KO) compared to wild‐type (WT) mice. Distal limb perfusion is significantly less in 40KO vs. WT mice despite comparable vascular density suggesting compromised temporal regulation of blood flow distribution in 40KO mice. Preliminary data suggested females of both genotypes were at greater risk than males for poor ischemic outcome. Using two models of surgically induced hindlimb ischemia, one preserving gracilis collaterals the other not (mild vs. severe surgery, respectively), we find that this dysregulated flow distribution, compromised arteriogenesis and persistent inflammation contribute to poor post‐surgery outcome in 40KO mice. The persistence (at 14 days) of activated macrophages in the 40KO ischemic limb is preceded by an earlier onset (8 vs. 12h) invasion of neutrophils, both consistent with the pro‐inflammatory phenotype of 40KO mice. Using the VCD model of induced ovarian failure to examine the role of estrogen in ischemic limb recovery, we find that recovery is further compromised in menopausal 40KO mice but improved in menopausal WT mice. Our data indicate that connexin 40 is necessary for recovery of ischemic limb perfusion and may act in synergy with estrogenregulated properties of the vasculature. Support: NIH R01HL058732