Downregulation of angiopoietin-1 and Tie2 in chronic hypoxic pulmonary hypertension.
BACKGROUND
Angiopoietins, newly discovered vascular-specific growth factors, and vascular endothelial growth factors (VEGF) play distinct and complementary roles in angiogenesis and vascular maturation. However, the exact roles of angiogenic factors in the adult pulmonary vasculature remain unclear.


OBJECTIVE
To elucidate possible roles of angiopoietins and VEGF in the development of hypoxic pulmonary hypertension (PH), changes in the expression of angiogenic factors were examined.


METHODS
The cellular distribution and expression of angiopoietins and their receptor Tie2 and VEGF were investigated by RT-PCR, immunoblot, and immunohistochemical methods in rat lung under normal and hypoxic conditions.


RESULTS
During the development of PH with vascular remodeling characterized by a decrease in vessel density of intrapulmonary arteries, protein expression of angiopoietin-1 (Ang-1), Tie2, and VEGF significantly decreased in the pulmonary arteries, and Tie2 receptor was inactivated in the lung. The expression of angiopoietin-3 (Ang-3), an endogenous antagonist of Ang-1, significantly increased in the intima under hypoxic conditions.


CONCLUSIONS
Since both Ang-1/Tie2 and VEGF promote angiogenesis and vascular survival, and play protective roles in the adaptation of microvascular changes during the onset of PH, the downregulation of both Ang-1/Tie2 and VEGF and upregulation of Ang-3 appear to be associated with vascular rarefaction and the development of hypoxic PH.
Yamamoto
Akihito
A
Department of Respiratory Medicine, Biomedical Research Center, Juntendo University School of Medicine, Tokyo, Japan.
Takahashi
Hideki
H
Kojima
Yuko
Y
Tsuda
Yasunari
Y
Morio
Yoshiteru
Y
Muramatsu
Masashi
M
Fukuchi
Yoshinosuke
Y
D042683:Angiopoietin-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D002908:Chronic Disease; D017931:DNA Primers; D015536:Down-Regulation / Q000502:physiology*; D006976:Hypertension, Pulmonary / Q000503:physiopathology*; D000860:Hypoxia / Q000378:metabolism; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008168:Lung / Q000098:blood supply / Q000378:metabolism; D008297:Male; D009389:Neovascularization, Pathologic / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010766:Phosphorylation; D011651:Pulmonary Artery / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D042787:Receptor, TIE-2 / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology
D042683:Angiopoietin-1; D017931:DNA Primers; D036341:Intercellular Signaling Peptides and Proteins; D042461:Vascular Endothelial Growth Factor A; D052250:Nitric Oxide Synthase Type III; D042787:Receptor, TIE-2; D053148:Caspase 3