Vascular endothelial growth factor-A specifies formation of native collaterals and regulates collateral growth in ischemia.
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.
Clayton
Jason A
JA
Department of Cell and Molecular Physiology, University of North Carolina, Chapel Hill, NC 27599-7545, USA.
Chalothorn
Dan
D
Faber
James E
JE
D000818:Animals; D002560:Cerebrovascular Circulation; D003097:Collateral Circulation; D004195:Disease Models, Animal; D005263:Femoral Artery / Q000601:surgery; D005838:Genotype; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D007511:Ischemia / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D007962:Leukocytes / Q000473:pathology; D008026:Ligation; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000098:blood supply*; D018919:Neovascularization, Physiologic; D010641:Phenotype; D012039:Regional Blood Flow; D015398:Signal Transduction; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism
D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2
Dev Biol. 2003 Oct 15;262(2):225-41
14550787
Trends Biochem Sci. 2003 Sep;28(9):488-94
13678960
Circulation. 2004 Oct 19;110(16):2424-9
15477417
Physiol Genomics. 2007 Jul 18;30(2):179-91
17426116
Eur J Clin Invest. 2007 Oct;37(10):755-66
17764463
Arterioscler Thromb Vasc Biol. 2008 Feb;28(2):322-8
18079407
Mol Biol Cell. 2008 Mar;19(3):994-1006
18094043
J Cell Mol Med. 2008 Aug;12(4):1284-302
18266966
Blood. 2004 Jun 15;103(12):4527-35
14982871
Nature. 1996 Apr 4;380(6573):435-9
8602241
Nature. 1996 Apr 4;380(6573):439-42
8602242
Am J Physiol. 1996 Oct;271(4 Pt 1):C1172-80
8897823
Dev Biol. 1999 Aug 15;212(2):307-22
10433823
Am J Physiol Heart Circ Physiol. 2005 Feb;288(2):H759-68
15471974
Am J Physiol Heart Circ Physiol. 2005 Aug;289(2):H947-59
15833801
Chest. 2005 Aug;128(2):787-91
16100168
Circulation. 2005 Oct 4;112(14):2108-13
16203926
Nature. 2005 Dec 8;438(7069):820-7
16341007
Am J Pathol. 2006 Feb;168(2):639-48
16436677
Microsc Res Tech. 2006 Feb;69(2):138-47
16456839
FASEB J. 2006 Mar;20(3):479-81
16423874
J Cell Mol Med. 2006 Jan-Mar;10(1):45-55
16563221
Circ Res. 2006 Apr 14;98(7):947-53
16527987
J Vasc Surg. 2006 Jul;44(1):166-75
16753278
Am J Cardiol. 2006 Nov 1;98(9):1194-7
17056326
FASEB J. 2006 Dec;20(14):2657-9
17095533
Development. 2000 Sep;127(18):3941-6
10952892
Am J Physiol Heart Circ Physiol. 2000 Oct;279(4):H1890-7
11009477
Int J Cancer. 2000 Nov 20;89(6):475-83
11102890
Circulation. 2000 Dec 19;102(25):3098-103
11120701
Cancer Res. 2001 Feb 1;61(3):1207-13
11221852
Circ Res. 2001 Oct 26;89(9):779-86
11679407
Development. 2002 Apr;129(8):1881-92
11934854
Nat Med. 2002 Aug;8(8):841-9
12091880
J Korean Med Sci. 2002 Oct;17(5):581-8
12378005
Genes Dev. 2002 Oct 15;16(20):2684-98
12381667
Br J Cancer. 2002 Nov 4;87(10):1057-65
12402142
Circ Res. 2003 Mar 7;92(4):378-85
12600898
Circulation. 2003 May 6;107(17):2213-20
12707241
Nat Med. 2003 Jun;9(6):669-76
12778165