Background: Recently, we reported that recovery of tissue perfusion in the ischemic hindlimb was reduced, inflammatory response increased, and survival of distal limb tissue compromised in Cx40-deficient (Cx40-/-) mice. Here we evaluate whether genotype-specific differences in tissue perfusion, native vascular density, arteriogenesis, blood pressure and chronic AT1R activation contribute to poor recovery of ischemic hindlimb tissue in Cx40-/- mice. Methods: Hindlimb ischemia was induced in wild-type (WT), Cx40-/-, and losartan treated Cx40-/- mice using surgical procedures that either maintained (mild surgery) or compromised (severe surgery) perfusion of major collateral vessels supplying the distal limb. Pre- and post-surgical hindlimb perfusion was evaluated and tissue survival, microvascular density and macrophage infiltration documented during recovery. Results: Hindlimb perfusion was compromised in pre-surgical Cx40-/- vs. WT mice despite comparable native microvascular density. Hindlimb perfusion 24h post-surgery in Cx40-/- and WT mice was comparable following mild surgery (collateral vessels maintained), but compromised arteriogenesis in Cx40-/- animals nevertheless limited subsequent recovery of tissue perfusion and compromised tissue survival. Prolonged pre- and post-surgical treatment of Cx40-/- mice with losartan (an AT1R antagonist) normalized blood pressure but did not improve tissue perfusion or survival, despite reduced macrophage infiltration. Conclusions: Cx40 is necessary for normal tissue perfusion and for recovery of perfusion, arteriogenesis and tissue survival in the ischemic hindlimb. Our data suggest that Cx40-/- mice are at significantly greater risk for poor recovery from ischemic insult due to compromised regulation of tissue perfusion, vascular remodeling, and prolonged inflammatory response.
- gap junction
- vascular remodeling
- collateral blood vessel
- Copyright © 2012, American Journal of Physiology - Heart and Circulatory Physiology