Elamaa, H., Kaakinen, M., Nätynki, M. et al. PHD2 deletion in endothelial or arterial smooth muscle cells reveals vascular cell type-specific responses in pulmonary hypertension and fibrosis. Angiogenesis 25, 259–274 (2022). https://doi.org/10.1007/s10456-021-09828-z
PHD2 deletion in endothelial or arterial smooth muscle cells reveals vascular cell type-specific responses in pulmonary hypertension and fibrosis
|Author:||Elamaa, Harri1,2; Kaakinen, Mika1,2; Nätynki, Marjut1,2;|
1Oulu Centre for Cell-Matrix Research, Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland
2Biocenter Oulu, University of Oulu, Oulu, Finland
3Medical Research Center Oulu, Research Unit of Biomedicine, University of Oulu and University Hospital Oulu, Oulu, Finland
|Online Access:||PDF Full Text (PDF, 9.5 MB)|
|Persistent link:|| http://urn.fi/urn:nbn:fi-fe2022042730813
|Publish Date:|| 2022-04-27
Hypoxia plays an important regulatory role in the vasculature to adjust blood flow to meet metabolic requirements. At the level of gene transcription, the responses are mediated by hypoxia-inducible factor (HIF) the stability of which is controlled by the HIF prolyl 4-hydroxylase-2 (PHD2). In the lungs hypoxia results in vasoconstriction, however, the pathophysiological relevance of PHD2 in the major arterial cell types; endothelial cells (ECs) and arterial smooth muscle cells (aSMCs) in the adult vasculature is incompletely characterized. Here, we investigated PHD2-dependent vascular homeostasis utilizing inducible deletions of PHD2 either in ECs (Phd2∆ECi) or in aSMCs (Phd2∆aSMC). Cardiovascular function and lung pathologies were studied using echocardiography, Doppler ultrasonography, intraventricular pressure measurement, histological, ultrastructural, and transcriptional methods. Cell intrinsic responses were investigated in hypoxia and in conditions mimicking hypertension-induced hemodynamic stress. Phd2∆ECi resulted in progressive pulmonary disease characterized by a thickened respiratory basement membrane (BM), alveolar fibrosis, increased pulmonary artery pressure, and adaptive hypertrophy of the right ventricle (RV). A low oxygen environment resulted in alterations in cultured ECs similar to those in Phd2∆ECi mice, involving BM components and vascular tone regulators favoring the contraction of SMCs. In contrast, Phd2∆aSMC resulted in elevated RV pressure without alterations in vascular tone regulators. Mechanistically, PHD2 inhibition in aSMCs involved actin polymerization -related tension development via activated cofilin. The results also indicated that hemodynamic stress, rather than PHD2-dependent hypoxia response alone, potentiates structural remodeling of the extracellular matrix in the pulmonary microvasculature and respiratory failure.
|Pages:||259 - 274|
|Type of Publication:||
A1 Journal article – refereed
|Field of Science:||
1182 Biochemistry, cell and molecular biology
Open Access funding provided by University of Oulu including Oulu University Hospital. Research was supported by the Academy of Finland Centre of Excellence Program (251314) for LE and JM, and the Academy Research Fellow Grant (136880) for LE.
|Academy of Finland Grant Number:||
251314 (Academy of Finland Funding decision)
136880 (Academy of Finland Funding decision)
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