| First Author | Kassa B | Year | 2021 |
| Journal | Am J Physiol Lung Cell Mol Physiol | Volume | 321 |
| Issue | 4 | Pages | L675-L685 |
| PubMed ID | 34346780 | Mgi Jnum | J:310431 |
| Mgi Id | MGI:6762451 | Doi | 10.1152/ajplung.00351.2020 |
| Citation | Kassa B, et al. (2021) Endothelial cell PHD2-HIF1alpha-PFKFB3 contributes to right ventricle vascular adaptation in pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 321(4):L675-L685 |
| abstractText | 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-HIF1alpha-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, HIF1alpha, or PFKFB3 all had evidence of impaired RV vascular adaptation following hypoxia PH challenge. PHD2-HIF1alpha-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. |
