Role of angiopoietin-1 in experimental and human pulmonary arterial hypertension.
BACKGROUND
The pulmonary microvasculature, consisting mainly of an endothelial cell (EC) monolayer and scant matrix support, is incompletely muscularized. Thus, the distal pulmonary arterioles may be predisposed to regression on exposure to environmental stresses (ie, hypoxia) and may be dependent on EC survival factors, like angiopoietin (Ang) 1, to attenuate the development of pulmonary arterial hypertension (PAH). In order to clarify the link between Ang1 expression and the development of PAH in patients, we also studied messenger RNA and protein expression in lung samples from healthy control subjects and patients with idiopathic PAH (IPAH) or PAH associated with other diseases (APAH).


METHODS
Ang/Tie2 gene expression was assessed in rats that had been exposed to hypoxia (ie, 10% O2) for 1, 3, or 7 days. In a separate experiment, the cell-based gene transfer of Ang1/Ang2 was performed, and the effects were evaluated in rats with hypoxia-induced PAH.


RESULTS
Hypoxia induced significant early increases in right ventricular systolic pressure (RVSP) and right ventricle/left ventricle-plus-septum mass ratio (RV/[LV + S]), with a significant decrease in Tie2 expression. Hypoxic rats receiving Ang1 demonstrated significant improvements in RVSP and RV/(LV + S), with a partial normalization in Tie2 protein levels. Robust Ang1 expression was observed in healthy human lungs. Furthermore, there were no significant changes in the levels of Ang1 or Ang2 in IPAH or APAH samples vs those in control subjects.


CONCLUSIONS
Decreased activity of the Tie2 pathway with hypoxia may contribute to PAH, possibly by loss of EC survival signaling, which can be overcome by Ang1 gene transfer.
Kugathasan
Lakshmi
L
Terrence Donnelly Heart Centre, Division of Cardiology, St. Michael's Hospital, Queen Wing, Toronto, ON, Canada, M5B 1W8.
Dutly
André E
AE
Zhao
Yidan D
YD
Deng
Yupu
Y
Robb
Malcolm J
MJ
Keshavjee
Shaf
S
Stewart
Duncan J
DJ
D042683:Angiopoietin-1 / Q000032:analysis / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D000818:Animals; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000502:physiology; D004797:Enzyme-Linked Immunosorbent Assay; D015870:Gene Expression; D018014:Gene Transfer Techniques; D006801:Humans; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000503:physiopathology*; D000860:Hypoxia / Q000503:physiopathology; D008168:Lung / Q000737:chemistry; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011916:Rats, Inbred F344; D042787:Receptor, TIE-2 / Q000032:analysis
D042683:Angiopoietin-1; D012333:RNA, Messenger; D042787:Receptor, TIE-2