Endothelial cell PHD2-HIF1a-PFKFB3 contributes to right ventricle vascular adaptation in pulmonary hypertension

Biruk Kassa, Rahul Kumar, Claudia Mickael, Linda Sanders, Christine Vohwinkel, Michael H. Lee, Sue Gu, Jens M. Poth, Kurt R. Stenmark, You Yang Zhao, Rubin M. Tuder, Brian B. Graham*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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-HIF1a-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, HIF1a, or PFKFB3 all had evidence of impaired RV vascular adaptation following hypoxia PH challenge. PHD2-HIF1a- 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.

Original languageEnglish (US)
Pages (from-to)L675-L685
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume321
Issue number4
DOIs
StatePublished - Oct 2021

Keywords

  • Pulmonary hypertension
  • Right ventricle
  • Stereology
  • Vascular adaptation

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

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