Pulmonary hypertension results in chronic pressure overload of the right ventricle (RV), which invariablyresults in right ventricular hypertrophy (RVF). Right heart failure (RHF) caused by a decompensatedhypertrophic response to pressure overload is the leading cause of death in patients with severepulmonary hypertension (SPH). Despite its profound clinical consequences, however, little is known aboutright ventricular adaptation and failure within the context of SPH. We propose an integrated physiological,cellular, and molecular approach to identifying the determinants of RHF in animal models of pulmonaryhypertension. While many animal models of pulmonary hypertension mimic some of the pulmonaryvascular changes associated with the human SPH and cause RV), few result in RHF. We show thatcombining chronic hypoxia with VEGF receptor blockade results in RVH that progresses to contractiledysfunction and maladaptive remodeling typical of HF, while chronic hypoxia alone produces a stable RVHand no RHF. In addition, applying VEGF receptor blockade to a pure hemodynamic stress (pulmonaryartery banding) worsens RV function. The RVF triggered by these manipulations is associated withdecreased NO bioavailability and alterations in the cGMP/PKG-1 signaling pathway that decrease itseffectiveness in suppressing hypertrophy and potentiating VEGF signaling. Reactivating cGMP/PKG-1signaling through chronic inhibition of the cGMP-specific phosphodiesterase 5A (PDE5AI) transforms the'pathological' hypertrophic response in the hypoxia/VEGFR2 blockade model to more closely match that of'physiological' hypertrophy, in which the fetal cardiac gene program is suppressed and myocyte growth islimited. Based on these preliminary data, we hypothesize that the VEGF/NO/cGMP signaling axiscoordinates the growth of the adult heart (hypertrophy) to produce a stable molecular and cellularresponse to adverse hemodynamic and/or neurohprmonal stress. Disruption of this signaling axisand the intercellular communication between cardiac myocytes and endothelial cells leads todecompensation, maladaptive remodeling, and heart failure.
Specific Aim #1 will determine whetherhemodynamic stress caused by PAH coupled with VEGF receptor blockade causes the transition fromadaptive RVH to RVF.
Specific Aim #2 will determine whether disruption of VEGF/NO/GMP signaling dueto underlying oxidative stress contributes to the maladaptive remodeling of the right heart and the transitionto RVF.
Specific Aim #3 will identify novel genetic modifiers of RVF in the setting of pulmonaryhypertension using consomic rat strains as a platform for genetic analysis. An understanding of the role ofVEGF/NO/cGMP pathway in RHF and the identification of QTLs that modify the extent or susceptibility tosuch dysfunction is a critical step in developing rationale therapies to prevent PAH-associated RVF. Project5 will be highly integrated with Project 4, and will provide mechanistic insights into mechanisms of RVdysfunction (Project 2) and potential biomarkers for Projects 1 and 3.
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