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Pressure Overload-Induced Ventricular Crosstalk Activates Regenerative Mechanisms in the Contralateral Ventricle in Neonatal Mice [scRNA-Seq]

ABSTRACT: Pulmonary artery banding (PAB) can restore left ventricular (LV) function in infants with end-stage LV dilated cardiomyopathy (LV-DCM), yet the underlying mechanisms remain unclear. Given the transient regenerative capacity of the neonatal heart, we investigated whether pressure overload in one ventricle activates adaptive and regenerative responses in the contralateral ventricle. We induced pressure overload in neonatal mice at postnatal day (P) 0-1 using pulmonary artery banding (nPAB) or transverse aortic constriction (nTAC). In both models, ventricular mass and wall thickness increased not only in the targeted ventricle but also in the contralateral ventricle. These changes were accompanied by cardiomyocyte hyperplasia, preserved systolic function, and enhanced angiogenesis without fibrosis. Bulk and single-nucleus RNA sequencing revealed coordinated activation of pro-proliferative and angiogenic gene programs in both ventricles, including expansion of a cycling cardiomyocyte subpopulation characterized by Ccnd2. In contrast, PAB at P7 resulted in maladaptive hypertrophy, fibrosis, loss of cardiomyocyte proliferation, and impaired biventricular function. These findings reveal an early-life window in which ventricular cross-talk enables a regenerative response to localized pressure overload, supporting the mechanistic rationale for clinical PAB in infants with LV-DCM.

ORGANISM(S): Mus musculus

PROVIDER: GSE312674 | GEO | 2026/04/21

REPOSITORIES: GEO

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Project description:Background: Right ventricular (RV) and left ventricular (LV) myocardium differ in their response to pressure-overload hypertrophy (POH). In this report we use microarray and proteomic analyses to identify pathways modulated by LV-, and RV-POH in the immature heart. Methods: Newborn New Zealand White rabbits underwent banding of the descending thoracic aorta (LV-POH; n=6). RV-POH was achieved by banding the pulmonary artery (n=6). Sham–control animals (SC; n=6 each) were sham-manipulated. Following 4 (LV-POH) and 6 weeks (RV-POH) recovery, the hearts were removed and matched sample RNA and proteins were isolated for microarray and proteomic analysis. Results: There was no difference in body weight in RV-, LV-POH vs. SC but there was a significant increase vs. SC in RV (3.2±0.8g vs. 1.2±0.3g; P<0.01) and LV weight (7.08±0.6g vs. 4.02±0.2g; P<0.01). Fractional area change (RV-POH) and shortening fraction (LV-POH) decreased significantly (23±6 vs. 47±6 and 21±4 vs.44±2, respectively, P<0.01). Microarray analysis demonstrated that LV-POH enriched pathways for oxidative phosphorylation, mitochondria energy pathways, actin, ILK, hypoxia, calcium and protein kinase-A signalling. RV-POH enriched pathways for cardiac oxidative phosphorylation. Proteomic analysis revealed 19 proteins were uniquely expressed in LV-POH vs. SC. Functional annotation clustering analysis indicated significant enrichment for the mitochondrion, cellular macromolecular complex assembly and oxidative phosphorylation. RV-POH had 15 uniquely expressed proteins vs. SC. Functional annotation clustering analysis indicated significant enrichment in structural constituents of muscle, cardiac muscle tissue development and calcium handling. Conclusion: Our results identify unique transcript and protein expression profiles in LV, RV-POH and provide new insight into the biological basis of ventricular specific hypertrophy. 3 different conditions: PAB-RV vs. Sham-control RV, PAB-RV [test] vs. PAB-LV [control], AOB-LV vs. Sham-control LV.

Project description:Aims: Cardiomyocyte-specific nitric oxide synthase 3 (NOS3) overexpression reduces left ventricular (LV) remodelling after myocardial infarction in mice, but its effect on sustained LV pressure-overload remains incompletely understood. We investigated LV structural and functional adaptation to elevated afterload in mice with cardiomyocyte-restricted NOS3 overexpression (NOS3TG) and wild type littermates (WT). Methods and Results: Hemodynamic indices, cardiac hypertrophy and interstitial fibrosis were measured 10 weeks after transverse aortic constriction (TAC). After 10 weeks TAC, NOS3TG had better preserved systolic function (maximum rates of pressure development normalized to maximal pressure 77Â±6 versus 65Â±2 ms-1, P=0.05), reduced heart weight-body weight ratio (HW/BW, 5.0Â±0.3 versus 5.8Â±0.1, P<0.05), and cardiomyocyte width than WT (14.9Â±0.4 vs 16.7Â±0.2 ?m, P<0.05). After 10 weeks TAC, a 44k cDNA chip-based microarray analysis was validated using real time PCR and revealed significantly altered expression pattern of genes involved in cellular growth, matrix remodelling, and inflammation between genotypes. Conclusions: Cardiomyocyte-restricted NOS3 overexpression attenuates TAC-induced hypertrophy via autocrine inhibition of cardiomyocyte cell growth, but does not mitigate myocardial fibrosis. The subsequent diastolic dysfunction suggests that inhibition of matrix producing cells during hypertrophic stress is necessary to prevent functional and structural deterioration of the pressure-overloaded heart. Left ventricular mRNA expression profiles were compared between alpha-myosin heavy chain driven nitric oxide synthase 3 (alpha-MHC-NOS3) transgenic and wild type (WT) littermate mice at baseline and 10 weeks after transversal aortic constrcition-induced pressure-overload. Biological repeats: n=4, two males and two females, for each group and condition. Transgenic mice were backcrossed for seven generations (F7) to a C57Bl/6 N background and age and weight matched animals were used for microarray experiments.

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Pressure Overload-Induced Ventricular Crosstalk Activates Regenerative Mechanisms in the Contralateral Ventricle in Neonatal Mice [scRNA-Seq]

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