Hypoxia‐driven proliferation of human pulmonary artery fibroblasts: cross‐talk between HIF‐1α and an autocrine angiotensin system

• Published in: The FASEB journal Vol. 19; no. 7; pp. 1 - 26
• Main Authors: Krick, Stefanie, Hänze, Jörg, Eul, Bastian, Savai, Rajkumar, Seay, Ulrike, Grimminger, Friedrich, Lohmeyer, Jürgen, Klepetko, Walter, Seeger, Werner, Rose, Frank
• Format: Journal Article
• Language: English
• Published: 01-05-2005
• Subjects: pulmonary hypertension; vascular remodeling
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.04-2890fje

ABSTRACT
Pulmonary artery adventitial fibroblasts (FBPA) may play a central role in lung vascular remodeling under conditions of hypoxia and inflammation, the result being pulmonary hypertension and cor pulmonale. In cultured human FBPA, both angiotensin II (Ang II) and hypoxia promoted cell cycle progression and cell proliferation and suppressed apoptosis. These effects were further enhanced when both stimuli were applied simultaneously. Hypoxia elevated the expression of hypoxia‐inducible factor 1α (HIF‐1α) and increased the expression of genes regulated by the hypoxia‐responsive element (HRE). Up‐regulation of both angiotensin‐converting enzyme (ACE) and Ang II receptor type 1 (AT1) was also observed. Exogenous Ang II further increased HIF/HRE‐dependent signaling in FBPA, whereas suppression of the autocrine ACE‐Ang II‐AT1 loop with inhibitors of ACE, AT1, and phosphatidylinositol 3‐kinase (PI3K) reduced the proliferative response to both hypoxia and exogenous Ang II. Overexpression of HIF‐1α by transient transfection caused the same proliferative effect and up‐regulation of AT1 expression that were observed under hypoxic conditions. In contrast, small interfering RNA targeting HIF‐1α inhibited hypoxia‐induced ACE and AT1 expression. Our studies indicate that the ACE‐Ang II‐AT1 system serves as a positive feedback loop and fosters FBPA proliferation under hypoxic conditions, with the PI3K‐HIF‐HRE axis as the central effector pathway. This pathway may thus facilitate vascular remodeling under hypoxic conditions.