Compromised regulation of tissue perfusion and arteriogenesis limit, in an AT1R-independent fashion, recovery of ischemic tissue in Cx40-/- mice

Jennifer S. Fang, Stoyan N. Angelov, Alex Simon, Janis M Burt

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

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 connexin 40 (Cx40)-deficient (Cx40-/-) mice. Here we evaluate whether genotype-specific differences in tissue perfusion, native vascular density, arteriogenesis, blood pressure, and chronic ANG II type 1 receptor (AT1R) activation contribute to poor recovery of ischemic hindlimb tissue in Cx40-/- mice. Hindlimb ischemia was induced in wild-type (WT), Cx40-/-, and losartan-treated Cx40-/- mice by using surgical procedures that either maintained (mild surgery) or compromised (severe surgery) perfusion of major collateral vessels supplying the distal limb. Preand postsurgical hindlimb perfusion was evaluated, and tissue survival, microvascular density, and macrophage infiltration were documented during recovery. Hindlimb perfusion was compromised in presurgical Cx40-/- versus WT mice despite comparable native microvascular density. Hindlimb perfusion 24 h postsurgery in Cx40-/- and WT mice was comparable after 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 postsurgical treatment of Cx40-/- mice with losartan (an AT1R antagonist) normalized blood pressure but did not improve tissue perfusion or survival, despite reduced macrophage infiltration. Thus it appears 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.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume304
Issue number6
DOIs
StatePublished - 2013

Fingerprint

Perfusion
Hindlimb
Tissue Survival
Losartan
connexin 40
Extremities
Macrophages
Blood Pressure
Blood Vessels
Ischemia
Genotype

Keywords

  • ANG II type 1 receptor
  • Collateral blood vessels
  • Connexin 40 deficient
  • Gap junction
  • Inflammation
  • Losartan
  • Vascular remodeling

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

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title = "Compromised regulation of tissue perfusion and arteriogenesis limit, in an AT1R-independent fashion, recovery of ischemic tissue in Cx40-/- mice",
abstract = "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 connexin 40 (Cx40)-deficient (Cx40-/-) mice. Here we evaluate whether genotype-specific differences in tissue perfusion, native vascular density, arteriogenesis, blood pressure, and chronic ANG II type 1 receptor (AT1R) activation contribute to poor recovery of ischemic hindlimb tissue in Cx40-/- mice. Hindlimb ischemia was induced in wild-type (WT), Cx40-/-, and losartan-treated Cx40-/- mice by using surgical procedures that either maintained (mild surgery) or compromised (severe surgery) perfusion of major collateral vessels supplying the distal limb. Preand postsurgical hindlimb perfusion was evaluated, and tissue survival, microvascular density, and macrophage infiltration were documented during recovery. Hindlimb perfusion was compromised in presurgical Cx40-/- versus WT mice despite comparable native microvascular density. Hindlimb perfusion 24 h postsurgery in Cx40-/- and WT mice was comparable after 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 postsurgical treatment of Cx40-/- mice with losartan (an AT1R antagonist) normalized blood pressure but did not improve tissue perfusion or survival, despite reduced macrophage infiltration. Thus it appears 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.",
keywords = "ANG II type 1 receptor, Collateral blood vessels, Connexin 40 deficient, Gap junction, Inflammation, Losartan, Vascular remodeling",
author = "Fang, {Jennifer S.} and Angelov, {Stoyan N.} and Alex Simon and Burt, {Janis M}",
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T1 - Compromised regulation of tissue perfusion and arteriogenesis limit, in an AT1R-independent fashion, recovery of ischemic tissue in Cx40-/- mice

AU - Fang, Jennifer S.

AU - Angelov, Stoyan N.

AU - Simon, Alex

AU - Burt, Janis M

PY - 2013

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N2 - 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 connexin 40 (Cx40)-deficient (Cx40-/-) mice. Here we evaluate whether genotype-specific differences in tissue perfusion, native vascular density, arteriogenesis, blood pressure, and chronic ANG II type 1 receptor (AT1R) activation contribute to poor recovery of ischemic hindlimb tissue in Cx40-/- mice. Hindlimb ischemia was induced in wild-type (WT), Cx40-/-, and losartan-treated Cx40-/- mice by using surgical procedures that either maintained (mild surgery) or compromised (severe surgery) perfusion of major collateral vessels supplying the distal limb. Preand postsurgical hindlimb perfusion was evaluated, and tissue survival, microvascular density, and macrophage infiltration were documented during recovery. Hindlimb perfusion was compromised in presurgical Cx40-/- versus WT mice despite comparable native microvascular density. Hindlimb perfusion 24 h postsurgery in Cx40-/- and WT mice was comparable after 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 postsurgical treatment of Cx40-/- mice with losartan (an AT1R antagonist) normalized blood pressure but did not improve tissue perfusion or survival, despite reduced macrophage infiltration. Thus it appears 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.

AB - 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 connexin 40 (Cx40)-deficient (Cx40-/-) mice. Here we evaluate whether genotype-specific differences in tissue perfusion, native vascular density, arteriogenesis, blood pressure, and chronic ANG II type 1 receptor (AT1R) activation contribute to poor recovery of ischemic hindlimb tissue in Cx40-/- mice. Hindlimb ischemia was induced in wild-type (WT), Cx40-/-, and losartan-treated Cx40-/- mice by using surgical procedures that either maintained (mild surgery) or compromised (severe surgery) perfusion of major collateral vessels supplying the distal limb. Preand postsurgical hindlimb perfusion was evaluated, and tissue survival, microvascular density, and macrophage infiltration were documented during recovery. Hindlimb perfusion was compromised in presurgical Cx40-/- versus WT mice despite comparable native microvascular density. Hindlimb perfusion 24 h postsurgery in Cx40-/- and WT mice was comparable after 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 postsurgical treatment of Cx40-/- mice with losartan (an AT1R antagonist) normalized blood pressure but did not improve tissue perfusion or survival, despite reduced macrophage infiltration. Thus it appears 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.

KW - ANG II type 1 receptor

KW - Collateral blood vessels

KW - Connexin 40 deficient

KW - Gap junction

KW - Inflammation

KW - Losartan

KW - Vascular remodeling

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JO - American Journal of Physiology

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