Natural killer cell TGF-β signaling influences pathological vascular remodeling in a mouse model of pulmonary hypertension — ASN Events
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  3. Natural killer cell TGF-β signaling influences pathological vascular remodeling in a mouse model of pulmonary hypertension

Natural killer cell TGF-β signaling influences pathological vascular remodeling in a mouse model of pulmonary hypertension (#163)

Declan J Gainer 1 , Kassandra M Coyle 1 , Matthew T Rätsep 2 , Kimberly Laverty 2 , Marty M VandenBroek 2 , Lindsay R Hilton 2 , Eric Vivier 3 4 , Mark L Ormiston 1 2
  1. Department of Medicine, Queen's University, Kingston, Ontario, Canada
  2. Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada
  3. Centre d'Immunologie de Marseille-Luminy, Marseille, France
  4. Aix-Marseille University, Marseille, France

Rationale: Pulmonary arterial hypertension (PAH) is a disease of occlusive vascular remodeling that is linked to innate immune dysfunction. Natural killer (NK) cells are cytotoxic innate lymphocytes which are known to influence vascular remodeling in both pregnancy and cancer, a functionality that is attributable to microenvironmental factors such as transforming growth factor-β (TGF-β) and hypoxia. Previous work has suggested that NK cells may have similar functions in the lung, with PAH arising as a disruption of the relationship between the pulmonary vasculature and NK cells. Although elevated TGF-β signaling has been linked to NK cell dysfunction in PAH, the specific contribution of this pathway to vascular remodeling in disease has not yet been explored.

Methods and Results: Ncr1-iCre mice, crossed with Tgfbr2fl/fl mice to produce offspring with TGF-β-insensitive NK cells (Tgfbr2NK-/-), were exposed to 10% O2 for 21 days as a model of pulmonary hypertension (PH). Male, but not female Tgfbr2NK-/- mice were partially protected from hypoxia-induced PH, defined as a lessened elevation of right ventricular (RV) systolic pressure and preserved RV function. Immunofluorescent staining of the pulmonary vasculature for ɑ-smooth muscle actin revealed no differences in arteriolar muscularization in hypoxic male Tgfbr2NK-/- mice, when compared to sex-matched controls. In contrast, naïve male Tgfbr2NK-/- mice possessed a thickened layer of atrial-derived cardiomyocytes surrounding their large pulmonary veins, implicating enhanced venous clearance as a potential cause of differential hemodynamics. Single-cell RNA sequencing of postnatal day 3 neonatal lungs identified the differential maturation of pulmonary venous cardiomyocytes in Tgfbr2NK-/- males, defined by the differential expression of cardiac troponin and myosin heavy chain isoforms.

Conclusions: Our findings identify NK cell TGF-β signaling as a contributor to pulmonary vascular homeostasis in both development and disease, and describe a potential sex-specific mechanistic role for pulmonary venous cardiomyocytes in hypoxia-induced pulmonary vascular remodeling.