Pulmonary arterial hypertension (PAH) is characterized by an increase of pulmonary vascular resistance leading to right ventricular overload and eventually to right ventricular failure and premature death. The pathological mechanisms underlying this condition remains incompletely understood. While the exact causes of PAH remain under investigation, it is widely recognized that the hallmarks of all forms of PH are sustained vasoconstriction, endothelium dysfunction and vascular remodeling. Remodeling of pulmonary arteries is characterized to varying degrees by thickening of the intimal and medial layer of muscular vessels resulting from proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs) with alterations in Ca2+ homeostasis. Diverse loss-of-function mutations in the conical BMPR2 gene, a component of the transforming growth factor beta (TGF?) family that plays a key role in cell growth and fibrosis, have been associated with the majority of familial and sporadic cases of PAH. We have shown that sarco(endo)plasmic reticulum Ca2+- ATPase 2a (SERCA2a) pump expression is decreased in small hypertrophied pulmonary arterioles from patients with PAH and in a rat model of monocrotaline (MCT)-induced PAH. We also found that SERCA2a expression is reduced in hypertrophied pulmonary arterial wall of patients with underlying BMPR2 mutations and in transgenic SM22-tet-BMPR2delx4 mice, with a SMC-specific mutant form of BMPR2, known to develop spontaneous PAH. Gene transfer of SERCA2a by an adenovirus resulted in decreased human PASMC proliferation and migration via a mechanism involving STAT3/NFAT signaling pathways. In addition, SERCA2a overexpression increased BMPR2, eNOS expression and activity and decreased STAT3/NFAT activity in hPAEC. In addition, selective pulmonary SERCA2a gene transfer using aerosolized adeno-associated virus serotype 1 (AAV1.SERCA2a) in MCT-PAH rat model attenuate pulmonary hypertension and RV hypertrophy, and increased eNOS and BMPR2 expression. Based upon the preliminary findings we contend there is cross talk between SERCA2a and BMPR2 with interdependent downstream signaling in pulmonary vascular that affects pulmonary vascular structural remodeling and suggest that SERCA2a gene transfer may modulate BMPR2 expression and/or dependent signaling pathways and therefore PAH phenotype. To test this hypothesis we will: 1) Characterize the link between SERCA2a and BMPR2 in pulmonary vascular cells. 2) Determine the effects of SERCA2-specific ablation in SMCs & ECs on PAH pathogenesis in a mouse model. And 3) Investigate the therapeutic effects of SERCA2a overexpression using chemically modified messenger RNA (modRNA) in transgenic animal models. The knowledge acquired through this proposal is significant because by modulating SERCA2a expression, we will characterize its key role in BMPR2 expression and signaling and therefore in pulmonary vascular remodeling and PAH phenotype, that may lead to the identification of new potential targets for therapeutic intervention to overcome the pathological feature of PAH.
The pathophysiology of pulmonary arterial hypertension (PAH) disease involves proliferation and migration of pulmonary artery smooth muscle cells (PASMC) and endothelium dysfunction. A decrease in expression of the calcium handling pump SERCA2a and BMPR2 are the major trigger for PASMC proliferation, which leads to vascular remodeling with increase of pulmonary and right ventricular pressures resulting in heart failure and death. Our goal is to attenuate pulmonary vascular remodeling by using SERCA2a gene therapy as a therapeutic approach to restore BMPR2 and reverse the pathological changes in PAH.
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