Endothelial HIF signaling regulates pulmonary fibrosis-associated pulmonary hypertension

Abstract

Pulmonary hypertension (PH) complicating chronic parenchymal lung disease, such as idiopathic pulmonary fibrosis, results in significant morbidity and mortality. Since the hypoxia-inducible factor (HIF) signaling pathway is important for development of pulmonary hypertension in chronic hypoxia, we investigated whether HIF signaling in vascular endothelium regulates development of PH related to pulmonary fibrosis. We generated a transgenic model in which HIF is deleted within vascular endothelial cells and then exposed these mice to chronic intraperitoneal bleomycin to induce PH associated with lung fibrosis. Although no differences in the degree of fibrotic remodeling were observed, we found that endothelial HIF-deficient mice were protected against development of PH, including right ventricle and pulmonary vessel remodeling. Similarly, endothelial HIF-deficient mice were protected from PH after a 4-wk exposure to normobaric hypoxia. In vitro studies of pulmonary vascular endothelial cells isolated from the HIF-targeted mice and controls revealed that endothelial HIF signaling increases endothelial cell expression of connective tissue growth factor, enhances vascular permeability, and promotes pulmonary artery smooth muscle cell proliferation and wound healing ability, all of which have the potential to impact the development of PH in vivo. Taken together, these studies demonstrate that vascular endothelial cell HIF signaling is necessary for development of hypoxia and pulmonary fibrosis associated PH. As such, HIF and HIF-regulated targets represent a therapeutic target in these conditions.

HIF1A up‐regulates the ADORA2B receptor on alternatively activated macrophages and contributes to pulmonary fibrosis

“…Although ADORA2B is expressed throughout the lung, we have demonstrated that ADORA2Bexpressing CD206 + macrophages are elevated in patients with IPF and in animal models of bleomycin-induced chronic lung disease (6). HIF1A stabilization in other cell types, including fibroblasts and endothelial cells, has been implicated in the development of pulmonary fibrosis and hypertension in models of bleomycin-induced lung injury (35,36). Furthermore, the presence of a hypoxia response element on the promoter of ADORA2B supports the notion that hypoxia through HIF1A will lead to up-regulation of ADORA2B, as described previously (23,28).…”

HIF‐prolyl hydroxylases as therapeutic targets in erythropoiesis and iron metabolism

“…Prolonged activation of the HIF system has profound effects on metabolic and cardiovascular homeostasis. 109 For example, HIF-2 has been implicated in the pathogenesis of pulmonary hypertension, [109][110][111][112][113][114] which raises concerns whether HIF-PHI therapy may adversely affect pulmonary artery pressure regulation in the CKD/ESRD patient population, which is characterized by a higher prevalence of pulmonary hypertension. 115 With regard to systemic blood pressure regulation, HIF-PHI therapy seems to be associated with a trend toward decreasing rather than increasing blood pressure.…”

A High-yield Isolation and Enrichment Strategy for Human Lung Microvascular Endothelial Cells

“…These reported techniques expand upon recently published protocols for the isolation of pulmonary MVEC. [14][15][16] The use of magnetic bead separation of MVEC is similar to the protocol previously published by Mackay et al 16 in which positive bead selection was used to achieve 1-9 million MVEC by passages 4-6 from 50 g of lung tissue, with the reported purity in the range of approximately 77-90%. Here we achieved 3 million cells, at low passage, from a small section of explanted lung, approximately 3 g.…”