This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 103/9/1027    most recent CIRCRESAHA.108.181115v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Clayton, J. A. Articles by Faber, J. E. Search for Related Content PubMed PubMed Citation Articles by Clayton, J. A. Articles by Faber, J. E. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Substance via MeSH Related Collections Angiogenesis Cerebrovascular disease/stroke Growth factors/cytokines Ischemic biology - basic studies Peripheral vascular disease Acute Cerebral Infarction Brain Circulation and Metabolism Related Article

(Circulation Research. 2008;103:1027.)
© 2008 American Heart Association, Inc.

Integrative Physiology

Vascular Endothelial Growth Factor-A Specifies Formation of Native Collaterals and Regulates Collateral Growth in Ischemia

Jason A. Clayton, Dan Chalothorn, James E. Faber

From the Department of Cell and Molecular Physiology, University of North Carolina, Chapel Hill.

Correspondence to James E. Faber, PhD, Department of Cell and Molecular Physiology, 111 Mason Farm Rd, University of North Carolina, Chapel Hill, NC 27599-7545. E-mail jefaber{at}med.unc.edu

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.

Key Words: arteriogenesis • angiogenesis • cerebral circulation • cerebral infarction • vascular development

Related Article:

Vascular Endothelial Growth Factor and the Collateral Circulation: The Story Continues

William M. Chilian and Yuh Fen Pung
Circ. Res. 2008 103: 905-906. [Extract] [Full Text] [PDF]

This article has been cited by other articles:

				J. Waltenberger Limits to Growth of Native Collateral Vessels: Just One Mouse CLIC Away From Unlimited Collateral Perfusion? Circ. Res., July 2, 2009; 105(1): 9 - 11. [Full Text] [PDF]

				D. Chalothorn, H. Zhang, J. E. Smith, J. C. Edwards, and J. E. Faber Chloride Intracellular Channel-4 Is a Determinant of Native Collateral Formation in Skeletal Muscle and Brain Circ. Res., July 2, 2009; 105(1): 89 - 98. [Abstract] [Full Text] [PDF]

				W. M. Chilian and Y. F. Pung Vascular Endothelial Growth Factor and the Collateral Circulation: The Story Continues Circ. Res., October 24, 2008; 103(9): 905 - 906. [Full Text] [PDF]