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A2071 - PTEN Depletion in Pulmonary Arteries Does Not Augment Chronic Hypoxia-Induced Pulmonary Arterial Pulmonary Hypertension
Author Block: G. B. Waypa, K. A. Smith, V. J. Dudley, P. T. Schumacker; Pediatrics and Neonatology, Northwestern University, Chicago, IL, United States.
Rationale: Chronic alveolar hypoxia (10% O2; 4 weeks) results in pulmonary hypertension (PH) characterized by pulmonary artery (PA) remodeling through thickening of the PA wall. Phosphatase and tensin homolog (PTEN) is a protein encoded by the PTEN gene. Mutations of this gene are present in many tumor types, as it negatively regulates cell growth. PTEN protein dephosphorylates phosphatidylinositol (3,4,5)-trisphosphate (PIP3) converting it to PIP2. This dephosphorylation results in inhibition of the PI3-kinase/AKT/mTOR signaling pathway thereby arresting cell proliferation. Therefore, we sought to test the hypothesis that the depletion of PTEN in pulmonary arteries augments chronic hypoxia (CH)-induced PA remodeling and thus augments PH.
Methods: Genetic deletion of PTEN from smooth muscle (SMC) was achieved by breeding SMC-heavy myosin chain-Cre expressing mice (SMC-MHC-Cre) with PTENflox/flox mice to generate SMC-MHC-Cre/PTENflox/flox mice. A double SMC and Endothelial cell (EC) knockout was also generated by crossing SMC-MHC-Cre/PTENflox/flox with VE-Cadherin-Cre mice (VE-Cre) to generate SMC-MHC-Cre/VE-Cre/PTENflox/flox mice. Tamoxifen was administered i.p. to activate Cre-mediated excision of the PTEN gene in targeted cells of adult mice. Control, SMC PTEN-, and SMC/EC PTEN-depleted mice were then exposed to either normoxia or CH (10% O2) for four weeks.
Results: In control mice CH increased PA wall thickness, induced PH as assessed by an increase in right ventricle systolic pressure (RVSP), and induced right ventricle hypertrophy (RVH) as assessed by Fulton’s Index. PTEN depletion in the SMC or SMC/EC of normoxic mice resulted in PA remodeling without subsequent changes in RVSP or RVH. Furthermore, SMC PTEN- or SMC/EC PTEN-depletion did not augment CH-induced changes in vascular remodeling, RVSP or RVH.
Conclusions: These results suggest that while depleting PTEN in PA can result in vascular remodeling, this morphological change does not augment the development of CH-induced pulmonary hypertension.