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Author Notes:

Kathy K. Griendling, PhD., Emory University, Division of Cardiology, 101 Woodruff Circle, WMB 308, Atlanta, GA 30322, Phone: 404-727-3364, kgriend@emory.edu

Authors reported no disclosures.

Subjects:

Research Funding:

This work was supported by National Institutes of Health grants HL38206 and HL095070.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Hematology
  • Peripheral Vascular Disease
  • Cardiovascular System & Cardiology
  • apoptosis
  • ischemia
  • metalloproteases
  • NADPH oxidase
  • neovascularization
  • MUSCLE-CELL-MIGRATION
  • NADPH OXIDASE
  • MATRIX METALLOPROTEINASES
  • MACROPHAGE ACCUMULATION
  • VESSEL DEVELOPMENT
  • COLLATERAL GROWTH
  • OXIDATIVE STRESS
  • PROGENITOR CELLS
  • ANGIOTENSIN-II
  • IN-VITRO

Polymerase delta-Interacting Protein 2 Promotes Postischemic Neovascularization of the Mouse Hindlimb

Tools:

Journal Title:

Arteriosclerosis, Thrombosis, and Vascular Biology

Volume:

Volume 34, Number 7

Publisher:

, Pages 1548-+

Type of Work:

Article | Post-print: After Peer Review

Abstract:

OBJECTIVE - Collateral vessel formation can functionally compensate for obstructive vascular lesions in patients with atherosclerosis. Neovascularization processes are triggered by fluid shear stress, hypoxia, growth factors, chemokines, proteases, and inflammation, as well as reactive oxygen species, in response to ischemia. Polymerase δ-interacting protein 2 (Poldip2) is a multifunctional protein that regulates focal adhesion turnover and vascular smooth muscle cell migration and modifies extracellular matrix composition. We, therefore, tested the hypothesis that loss of Poldip2 impairs collateral formation. APPROACH AND RESULTS - The mouse hindlimb ischemia model has been used to understand mechanisms involved in postnatal blood vessel formation. Poldip2+/- mice were subjected to femoral artery excision, and functional and morphological analysis of blood vessel formation was performed after injury. Heterozygous deletion of Poldip2 decreased the blood flow recovery and spontaneous running activity at 21 days after injury. H 2O2 production, as well as the activity of matrix metalloproteinases-2 and -9, was reduced in these animals compared with Poldip2+/+ mice. Infiltration of macrophages in the peri-injury muscle was also decreased; however, macrophage phenotype was similar between genotypes. In addition, the formation of capillaries and arterioles was impaired, as was angiogenesis, in agreement with a decrease in proliferation observed in endothelial cells treated with small interfering RNA against Poldip2. Finally, regression of newly formed vessels and apoptosis was more pronounced in Poldip2+/- mice. CONCLUSIONS - Together, these results suggest that Poldip2 promotes ischemia-induced collateral vessel formation via multiple mechanisms that likely involve reactive oxygen species-dependent activation of matrix metalloproteinase activity, as well as enhanced vascular cell growth and survival.

Copyright information:

© 2014 American Heart Association, Inc.

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