Impaired angiogenesis in SHR is associated with decreased KDR and MT1-MMP expression.
This study examined whether retarded angiogenesis in a hypertension animal model was associated with impaired VEGF signaling. Furthermore, we sought to determine whether this impairment could be overcome by VEGF addition. Using a rat sponge implantation model, we confirmed impaired angiogenesis in spontaneous hypertensive rats (SHRs). Fourteen days after sponge implantation, the level of angiogenesis in SHRs was approximately half of those in age-matched normotensive Wistar-Kyoto or Sprague-Dawley rats. Significantly, expression of kinase-insert domain-containing receptor (KDR) and membrane type 1 matrix metalloproteinase (MT1-MMP) was reduced in SHRs compared to controls. Immunohistological analysis indicated endothelial proliferation was decreased in SHRs. Gene transfer of human VEGF(121) increased KDR and MT1-MMP expression in SHRs. VEGF(121) also up-regulated endothelial proliferation and angiogenesis. Our results indicate down-regulated KDR and MT1-MMP expression is associated with an impaired angiogenesis in SHRs. VEGF gene transfer is effective in ameliorating the impaired angiogenesis in SHRs.
Wang
He
H
Human Biomarker Center, Translational Medicine and Technology, GlaxoSmithKline, USA. he.4.wang@gsk.com
Olszewski
Bronia
B
Rosebury
Wendy
W
Wang
Dongkai
D
Robertson
Andrew
A
Keiser
Joan A
JA
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002455:Cell Division; D018076:DNA, Complementary / Q000378:metabolism; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D018014:Gene Transfer Techniques; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000096:biosynthesis*; D009389:Neovascularization, Pathologic; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013053:Spectrophotometry; D013997:Time Factors; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000096:biosynthesis*
D018076:DNA, Complementary; D018809:Proliferating Cell Nuclear Antigen; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases