Vascular endothelial growth factor-A specifies formation of native collaterals and regulates collateral growth in ischemia.

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  • Author(s): Clayton JA;Clayton JA; Chalothorn D; Faber JE
  • Source:
    Circulation research [Circ Res] 2008 Oct 24; Vol. 103 (9), pp. 1027-36. Date of Electronic Publication: 2008 Sep 18.
  • Publication Type:
    Comparative Study; Journal Article; Research Support, N.I.H., Extramural
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: Lippincott Williams & Wilkins Country of Publication: United States NLM ID: 0047103 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1524-4571 (Electronic) Linking ISSN: 00097330 NLM ISO Abbreviation: Circ Res Subsets: MEDLINE
    • Publication Information:
      Publication: Baltimore, MD : Lippincott Williams & Wilkins
      Original Publication: Baltimore, Md. Grune & Stratton.
    • Subject Terms:
      Cerebrovascular Circulation* ; Collateral Circulation* ; Neovascularization, Physiologic*; Infarction, Middle Cerebral Artery/*metabolism ; Ischemia/*metabolism ; Muscle, Skeletal/*blood supply ; Vascular Endothelial Growth Factor A/*metabolism ; Vascular Endothelial Growth Factor Receptor-1/*metabolism; Animals ; Disease Models, Animal ; Femoral Artery/surgery ; Genotype ; Infarction, Middle Cerebral Artery/pathology ; Infarction, Middle Cerebral Artery/physiopathology ; Ischemia/pathology ; Ischemia/physiopathology ; Leukocytes/pathology ; Ligation ; Mice ; Mice, Transgenic ; Phenotype ; Regional Blood Flow ; Signal Transduction ; Time Factors ; Vascular Endothelial Growth Factor A/genetics ; Vascular Endothelial Growth Factor Receptor-1/deficiency ; Vascular Endothelial Growth Factor Receptor-1/genetics ; Vascular Endothelial Growth Factor Receptor-2/genetics ; Vascular Endothelial Growth Factor Receptor-2/metabolism
    • Abstract:
      The density of native (preexisting) collaterals and their capacity to enlarge into large conduit arteries in ischemia (arteriogenesis) are major determinants of the severity of tissue injury in occlusive disease. Mechanisms directing arteriogenesis remain unclear. Moreover, nothing is known about how native collaterals form in healthy tissue. Evidence suggests vascular endothelial growth factor (VEGF), which is important in embryonic vascular patterning and ischemic angiogenesis, may contribute to native collateral formation and arteriogenesis. Therefore, we examined mice heterozygous for VEGF receptor-1 (VEGFR-1(+/-)), VEGF receptor-2 (VEGFR-2(+/-)), and overexpressing (VEGF(hi/+)) and underexpressing VEGF-A (VEGF(lo/+)). Recovery from hindlimb ischemia was followed for 21 days after femoral artery ligation. All statements below are P<0.05. Compared to wild-type mice, VEGFR-2(+/-) showed similar: ischemic scores, recovery of hindlimb perfusion, pericollateral leukocytes, collateral enlargement, and angiogenesis. In contrast, VEGFR-1(+/-) showed impaired: perfusion recovery, pericollateral leukocytes, collateral enlargement, worse ischemic scores, and comparable angiogenesis. Compared to wild-type mice, VEGF(lo/+) had 2-fold lower perfusion immediately after ligation (suggesting fewer native collaterals which was confirmed by angiography) and blunted recovery of perfusion. VEGF(hi/+) mice had 3-fold greater perfusion immediately after ligation, more native collaterals, and improved recovery of perfusion. These differences were confirmed in the cerebral pial cortical circulation where, compared to VEGF(hi/+) mice, VEGF(lo/+) formed fewer collaterals during the perinatal period when adult density was established, and had 2-fold larger infarctions after middle cerebral artery ligation. Our findings indicate VEGF and VEGFR-1 are determinants of arteriogenesis. Moreover, we describe the first signaling molecule, VEGF-A, that specifies formation of native collaterals in healthy tissues.
    • Comments:
      Comment in: Circ Res. 2008 Oct 24;103(9):905-6. (PMID: 18948626)
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    • Grant Information:
      F32 HL080847 United States HL NHLBI NIH HHS; R01 HL090655 United States HL NHLBI NIH HHS; R01 HL062584 United States HL NHLBI NIH HHS; R01 HL090655-01A1 United States HL NHLBI NIH HHS; T32-HL069768 United States HL NHLBI NIH HHS; T32 HL069768 United States HL NHLBI NIH HHS; F32-HL080847 United States HL NHLBI NIH HHS; HL62584 United States HL NHLBI NIH HHS
    • Accession Number:
      0 (Vascular Endothelial Growth Factor A)
      0 (vascular endothelial growth factor A, mouse)
      EC 2.7.10.1 (Vascular Endothelial Growth Factor Receptor-1)
      EC 2.7.10.1 (Vascular Endothelial Growth Factor Receptor-2)
    • Publication Date:
      Date Created: 20080920 Date Completed: 20081106 Latest Revision: 20220310
    • Publication Date:
      20240829
    • Accession Number:
      PMC2729271
    • Accession Number:
      10.1161/CIRCRESAHA.108.181115
    • Accession Number:
      18802023