Role of ANG II in coronary capillary angiogenesis at the insulin-resistant stage of a NIDDM rat model.
With the use of Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of human non-insulin-dependent diabetes mellitus (NIDDM), we assessed whether ANG II is involved in coronary capillary angiogenesis at the insulin-resistant stage of NIDDM (20 wk of age). In OLETF rats, ANG II labeling and angiotensin type 1 (AT(1)) receptor expression in coronary vessels were increased more than in nondiabetic controls. A marked increase in vascular expression of vascular endothelial growth factor (VEGF) at both mRNA and protein levels was found in OLETF rats. The increased expression level of VEGF was associated with accumulation of hypoxia-inducible factor-1alpha (HIF-1alpha) activated by increased advanced glycation end products (AGEs). Morphometric analysis showed a significantly increased total coronary capillary density, which was a result of arterialization of the venular capillary portion in OLETF rats. Treatment of OLETF rats with candesartan, an AT(1) receptor blocker, inhibited vascular expressions of VEGF, HIF-1alpha, and AGEs, and ameliorated the morphometric changes. These results suggest a key role of ANG II in the pathogenesis of the coronary capillary remodeling in this NIDDM model.
Jesmin
Subrina
S
Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Sapparo, Japan.
Hattori
Yuichi
Y
Sakuma
Ichiro
I
Mowa
Chishimba N
CN
Kitabatake
Akira
A
D000804:Angiotensin II / Q000378:metabolism*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D002196:Capillaries / Q000166:cytology / Q000502:physiology; D003326:Coronary Circulation / Q000502:physiology*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000503:physiopathology*; D004195:Disease Models, Animal; D016228:Endothelial Growth Factors / Q000235:genetics / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000502:physiology; D017127:Glycation End Products, Advanced / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007333:Insulin Resistance / Q000502:physiology*; D008222:Lymphokines / Q000235:genetics / Q000378:metabolism; D008297:Male; D018919:Neovascularization, Physiologic / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D020334:Rats, Inbred OLETF; D020318:Rats, Long-Evans; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin / Q000235:genetics / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000235:genetics / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor; D013777:Tetrazoles / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D016228:Endothelial Growth Factors; D016326:Extracellular Matrix Proteins; D017127:Glycation End Products, Advanced; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008222:Lymphokines; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin; D017978:Receptors, Growth Factor; D013777:Tetrazoles; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000804:Angiotensin II; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor; C081643:candesartan