Hypoxic pulmonary artery fibroblasts trigger proliferation of vascular smooth muscle cells‐role of hypoxia‐inducible transcription factors

Abstract

Chronic lung hypoxia causes vascular remodeling with pulmonary artery smooth muscle cell (SMCPA) hyperplasia, resulting in pulmonary hypertension and cor pulmonale. We investigated SMCPA and pulmonary artery adventitial fibroblasts (FBPA) for their proliferative response to hypoxia. Strong SMCPA growth occurred under hypoxic conditions in SMCPA/FBPA co-cultures, but not in SMCPA monocultures. SMCPA growth was fully reproduced by transferring serum-free supernatant from hypoxic cultured FBPA to normoxic SMCPA. Hypoxia-inducible-transcription-factor subtypes (HIF-1alpha, HIF-2alpha, HIF-3alpha) and its dependent target genes, carrying the hypoxia-responsive-element as regulatory component, were strongly activated in both hypoxic FBPA and SMCPA. HIF-transcription-factor decoy technique, employed to FBPA during hypoxic culturing, blocked the mitogenic activity of FBPA conditioned medium on SMCPA. The data suggest that hypoxia-driven gene regulation in pulmonary artery fibroblasts results in a mitogenic stimulus on adjacent pulmonary artery smooth muscle cells, and HIF-transcription-decoy may offer a new therapeutic approach to suppress these events.

Hypoxia upregulates hypoxia inducible factor (HIF)-3α expression in lung epithelial cells: characterization and comparison with HIF-1α

“…High steady-state mRNA levels of HIF-3α were achieved in alveolar epithelial cells during sustained hypoxia. This finding supports earlier results which showed the abundantly expressed levels of HIF-3α mRNA in human pulmonary artery cells during hypoxia (1% O 2 , 24h) [39]. In previous studies, we demonstrated that HIF-1α mRNA and protein levels decreased in rat pulmonary artery cells during sustained hypoxia [40], thereby suggesting HIF-3α played an important role in lung responding to hypoxic damage.…”

Constitutive upregulation of hypoxia-inducible factor-1α mRNA occurring in highly metastatic lung carcinoma cells leads to vascular endothelial growth factor overexpression upon hypoxic exposure

“…Therefore, HIF-1a could be an important target for preventing metastasis. As such, suppression of HIF-1a, employing the techniques such as the transmission decoy technique (Rose et al, 2002), would be intriguing to suppress tumor metastasis.…”

Interferon Regulatory Factor-1 Regulates the Autophagic Response in LPS-Stimulated Macrophages through Nitric Oxide

“…While hypoxia-induced remodeling is associated with medial hypertrophy, direct stimulation of SMC proliferation by hypoxia remains somewhat controversial (37). Although there are reports of hypoxia driven smooth muscle cell proliferation (38,39), several in vitro studies have shown that hypoxia does not directly increase SMC proliferation (40)(41)(42) or may actually decrease proliferation (43,44). However, fibroblasts that are less differentiated than the other two main vascular cell types, have a greater proliferative response to hypoxia (44)(45)(46).…”

“…Although there are reports of hypoxia driven smooth muscle cell proliferation (38,39), several in vitro studies have shown that hypoxia does not directly increase SMC proliferation (40)(41)(42) or may actually decrease proliferation (43,44). However, fibroblasts that are less differentiated than the other two main vascular cell types, have a greater proliferative response to hypoxia (44)(45)(46). Fibroblasts are uniquely positioned in the scheme of remodeling being able to rapidly proliferate, contract, migrate, synthesize cytokines and other mediators, and transdifferentiate into other cell types such as the SMC-like myofibroblast (47).…”