Abstract Body (Do not enter title and authors here): Background: Pulmonary arterial hypertension (PAH) is a disastrous disease that is characterized by high blood pressure in the pulmonary arteries which has the potential to lead to heart failure over time. Previously, our lab found that endothelial-specific knockout of Egln1, encoding prolyl 4-hydroxylase-2 (PHD2), induced spontaneous pulmonary hypertension (PH). Recently, we elucidated that Tmem100 is a lung-specific endothelial gene using Tmem100^CreERT2 mice. We reason that lung endothelial-specific deletion of Egln1 could lead to the development of PH without affecting other organs’ Egln1 gene expression and defect.
Methods: Tmem100-CreERT2 mice were crossed with Egln1^flox/flox mice to generate Egln1^f/f; Tmem100 CreERT2 (LiCKO) mice. Western blot and immunofluorescent staining were performed to verify the knockout efficacy of Egln1 in multiple organs of LiCKO mice. PH phenotypes including hemodynamics, right heart size and function, and pulmonary vascular remodeling were evaluated by right heart catheterization and echocardiography measurement.
Results: Tamoxifen treatment induced Egln1 deletion in the lung ECs but no other organs in adult LiCKO mice. LiCKO mice exhibited an increase in right ventricular systolic pressure (RVSP, ~35 mmHg) and right heart hypertrophy. Echocardiography measurement showed right heart hypertrophy and cardiac and pulmonary arterial dysfunction. Pulmonary vascular remodeling including pulmonary wall thickness and muscularization of distal pulmonary arterials was enhanced in LiCKO mice compared to wild-type mice.
Conclusions: Tmem100 promoter-mediated lung endothelial knockout of Egln1 in mice develops spontaneous PH. LiCKO mice could be a novel mouse model for PH to study lung and other organ crosstalk.