title: Hypoxia-inducible factor-1alpha/vascular endothelial growth factor pathway for adventitial vasa vasorum formation in hypertensive rat aorta.
abstract: The roles of adventitial vasa vasorum have been highlighted in vascular wall homeostasis. Vascular endothelial growth factor (VEGF) is a potent angiogenic factor in physiological and pathophysiological conditions. However, little is known regarding the changes in adventitial vasa vasorum and the mechanism of the formation in hypertensive arteries. Accordingly, endothelial cell proliferation, adventitial vasa vasorum count, and expression of VEGF signaling axis proteins were examined in the ascending aorta of hypertensive Wistar rats that underwent suprarenal aortic constriction. Hypertension not only induced medial and adventitial thickening but also significantly increased adventitial vasa vasorum count by day 28. Preceding the medial thickening, BrdU(+)-proliferative endothelial cells were observed in the adventitia but not in the media and intima after day 3; they peaked at day 7 and remained modestly increased at day 28. The BrdU(+) endothelial cells showed induction of Ets-1, a transcription factor mediating angiogenic response of VEGF. Furthermore, concomitant expression of VEGF and a hypoxia-inducible transcription factor (HIF-1alpha) was observed in the outer layers of medial smooth muscle cells at day 3 and extended to the middle layers of medial smooth muscle cells at day 7, returning to lower levels by day 28. In conclusion, adventitial vasa vasorum formation was induced by hypertension through the HIF-1alpha/VEGF/Ets-1 pathway during hypertensive remodeling.
authors.affiliation: Cardiovascular Research Institute and Internal Medicine III, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Kuwahara
authors.forename: Hisashi
authors.initials: H
authors.lastname: Kai
authors.forename: Keisuke
authors.initials: K
authors.lastname: Tokuda
authors.forename: Rei
authors.initials: R
authors.lastname: Shibata
authors.forename: Ken
authors.initials: K
authors.lastname: Kusaba
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Tahara
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Niiyama
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Nagata
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Imaizumi
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000378:metabolism / Q000473:pathology; D001794:Blood Pressure / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000502:physiology*; D016228:Endothelial Growth Factors / Q000096:biosynthesis / Q000502:physiology*; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D006973:Hypertension / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D015151:Immunoblotting; D008222:Lymphokines / Q000096:biosynthesis / Q000502:physiology*; D008297:Male; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000502:physiology*; D050784:Proto-Oncogene Protein c-ets-1; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000502:physiology; D050783:Proto-Oncogene Proteins c-ets; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000096:biosynthesis / Q000502:physiology; D014651:Vasa Vasorum / Q000378:metabolism / Q000473:pathology*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D004268:DNA-Binding Proteins; D016228:Endothelial Growth Factors; C494043:Ets1 protein, rat; C497444:Hif1a protein, rat; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008222:Lymphokines; D009687:Nuclear Proteins; D050784:Proto-Oncogene Protein c-ets-1; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors