Exploring the contribution of natural killer cell TGFβ signaling to pulmonary vascular development and the pathogenesis of hypoxia-induced pulmonary hypertension

Abstract

Background: Proper immune functioning is crucial for lung development and vascular stability; deviations to these processes may lead to complications, including bronchopulmonary dysplasia (BPD) and pulmonary arterial hypertension (PAH). BPD is a disease of prematurity that is characterized by underdeveloped distal airways and a truncated pulmonary circulation. It is associated with significant neonatal morbidity and mortality, as well as several respiratory complications later in life. PAH is a disease of obstructive vascular remodeling that is characterized by the cancer-like proliferation of pulmonary endothelial and vascular smooth muscle cells. This obstruction increases the pressure in the pulmonary vasculature, putting strain on the right heart, and leading to death in ~15% of cases each year. Both BPD and PAH are thought to be linked to immune dysfunction. Natural killer (NK) cells are cytotoxic type I innate lymphoid cells that can promote vascular remodeling in both pregnancy and cancer in response to microenvironmental cues, such as hypoxia and transforming growth factor (TGF)-β. Previous work has indicated that NK cells may have similar functions in the lung, supporting the suggestion that BPD and PAH may arise as a result of disruptions in the relationship between NK cells and the pulmonary endothelium. However, the precise contribution of NK cells to the pathogenesis of BPD and PAH and the molecular pathways governing their contribution have not yet been defined. This study explored the hypothesis that TGFβ signaling in NK cells is an essential contributor to normal vascular development in the lung and drives pathological pulmonary vascular remodeling in PAH. Results: Studies used mice bearing a conditional deletion of Tgfbr2 in NK cells (Tgfbr2NK-/-). Tgfbr2NK-/- mice had a reduction of pre-capillary pulmonary arterioles relative to littermate controls, accompanied by a baseline increase in right ventricular (RV) systolic pressure in adult Tgfbr2NK-/- mice and the presentation of a BPD-like phenotype in Tgfbr2NK-/- pups by postnatal day 7. Despite this developmental defect, male, but not female Tgfbr2NK-/- mice exposed to chronic hypoxia were partially protected from developing pulmonary hypertension. We revealed elevated pSMAD2/3 and RV accumulation for hypoxic NK cells in male, but not female mice. Conclusion: Our results identify NK TGFβ signaling as a critical contributor to pulmonary vascular remodeling in both development and disease, as well as a sex-specific role for NK cells in hypoxia-induced pulmonary vascular remodeling.