Endothelial cell PHD2-HIF1α-PFKFB3 contributes to right ventricle vascular adaptation in pulmonary hypertension
| Autor: | Linda Sanders, Kurt R. Stenmark, Rubin M. Tuder, You Yang Zhao, Brian B. Graham, Biruk Kassa, Sue Gu, Rajesh Kumar, Claudia Mickael, Michael H. Lee, Christine Vohwinkel, Jens M. Poth |
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| Rok vydání: | 2021 |
| Předmět: |
Pulmonary and Respiratory Medicine
medicine.medical_specialty Capillary growth Physiology Phosphofructokinase-2 Heart Ventricles Hypertension Pulmonary Neovascularization Physiologic Stereology Hypoxia-Inducible Factor-Proline Dioxygenases Mice Physiology (medical) Internal medicine Medicine Animals Anaerobiosis Mice Knockout business.industry Endothelial Cells Cell Biology RV hypertrophy medicine.disease Hypoxia-Inducible Factor 1 alpha Subunit Pulmonary hypertension Coronary Vessels Endothelial stem cell Mice Inbred C57BL medicine.anatomical_structure Ventricle Cardiology Female Adaptation business Signal Transduction Research Article |
| Zdroj: | Am J Physiol Lung Cell Mol Physiol |
| ISSN: | 1522-1504 |
| Popis: | Humans and animals with pulmonary hypertension (PH) show right ventricular (RV) capillary growth, which positively correlates with overall RV hypertrophy. However, molecular drivers of RV vascular augmentation in PH are unknown. Prolyl hydroxylase (PHD2) is a regulator of hypoxia-inducible factors (HIFs), which transcriptionally activates several proangiogenic genes, including the glycolytic enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3). We hypothesized that a signaling axis of PHD2-HIF1α-PFKFB3 contributes to adaptive coupling between the RV vasculature and tissue volume to maintain appropriate vascular density in PH. We used design-based stereology to analyze endothelial cell (EC) proliferation and the absolute length of the vascular network in the RV free wall, relative to the tissue volume in mice challenged with hypoxic PH. We observed increased RV EC proliferation starting after 6 h of hypoxia challenge. Using parabiotic mice, we found no evidence for a contribution of circulating EC precursors to the RV vascular network. Mice with transgenic deletion or pharmacological inhibition of PHD2, HIF1α, or PFKFB3 all had evidence of impaired RV vascular adaptation following hypoxia PH challenge. PHD2-HIF1α-PFKFB3 contributes to structural coupling between the RV vascular length and tissue volume in hypoxic mice, consistent with homeostatic mechanisms that maintain appropriate vascular density. Activating this pathway could help augment the RV vasculature and preserve RV substrate delivery in PH, as an approach to promote RV function. |
| Databáze: | OpenAIRE |
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