Rationale: Pulmonary arterial hypertension (PAH) is a progressive and fatal disease in which elevated pulmonary arterial pressure (PAP) is caused by increased pulmonary vascular resistance (PVR). Pulmonary vascular remodeling due to enhanced pulmonary arterial smooth muscle cell (PASMC) proliferation is one of the leading causes for elevated PVR in PAH. mTOR signaling has been shown to regulate vascular smooth muscle cell proliferation and apoptosis. This study aims to investigate whether mTOR complexities in PASMC contribute to pulmonary vascular remodeling.
Methods: Inducible and smooth muscle cell conditional gene knockout mice of mTOR, Raptor, and Rictor were created by crossbreeding floxed mice with SMMHC-CreERT2 mice, in which a tamoxifen-inducible Cre recombinase was under the control of the smooth muscle myosin heavy chain promoter. Eight weeks old male knockout (KO) mice and wild-type (WT) control mice were exposed to 10% oxygen or normoxia control for three weeks (n≥5 in each group). Pulmonary vascular remodeling was evaluated using tissue morphometrics. Right ventricle systolic pressure (RVSP) and RV/(LV+S) were measured to evaluate pulmonary hypertensive changes. The PAP was measured using the isolated perfused/ventilated lung system. Isolated PASMC were obtained from WT and KO mice to investigate cell proliferation.
Results: The smooth muscle-specific deletion of mTOR, Raptor or Rictor in mice significantly decreased the expression levels of the target protein in pulmonary arterial tissue and aortic tissue. Deletion of mTOR or Raptor in vascular smooth muscle cells significantly attenuated the development of PH. In Rictor conditional KO mice, however, chronic hypoxia-mediated PH was comparable to the WT mice. The hypoxia-induced increases in RVSP, right ventricular hypertrophy, and small pulmonary arterial wall thickness in smooth muscle-specific Rictor KO mice were similar to the values obtained in the WT littermates.
Conclusion: This study identified no significant difference in the development of hypoxia-induced PH between smooth muscle specific Rictor KO mice and their WT littermates. This data indicates that Rictor in PASMC is not a predominant signaling pathway for the development and progression of PH.