Matsiukevich, D. | bioRxiv Science

bioRxiv2026

Angiotensin II–Driven Coronary Vasculopathy and Pressure-Overload Myocardial Remodeling Represent Distinct Vascular Phenotypes

ObjectiveChronic activation of the renin-angiotensin-aldosterone system (RAAS) promotes pathological remodeling of both myocardium and coronary arteries, yet the mechanisms that distinguish myocardial from vascular remodeling remain poorly defined. This study dissects the relative contributions of hemodynamic versus neurohumoral stress to cardiac remodeling, with emphasis on coronary vasculopathy and vascular smooth muscle cell (VSMC) plasticity. MethodsThree murine models were used: transverse aortic constriction (TAC), angiotensin II (AngII) plus phenylephrine (AngII/PE), and high-dose angiotensin II (HD-AngII). Hemodynamics were assessed by catheterization at early and late time points. Histological and immunostaining analyses quantified interstitial and perivascular remodeling, including cardiomyocyte hypertrophy, interstitial and perivascular fibrosis, VSMC phenotype transitions, proliferation and quiescence markers, and neointimal and elastic lamina remodeling. ResultsAfter 28 days, all models exhibited diastolic dysfunction and myocardial fibrosis. Systolic pressure averaged [~]130 mmHg in both AngII models versus [~]200 mmHg in TAC. Despite lower pressure, myocardial fibrosis was greater in AngII/PE and HD-AngII models. While TAC induced uniform cardiomyocyte hypertrophy, hypertrophy in AngII models localized near fibrotic and perivascular regions. Increasing AngII dosage shifted remodeling from predominantly myocardial to predominantly vascular phenotypes, accompanied by VSMC dedifferentiation, proliferation, centripetal migration across the internal elastic lamina, neointima formation, elastic lamina disruption, and increased circulating desmosine, consistent with elastin degradation. AKT signaling was selectively increased in coronary VSMCs during this vasculopathic remodeling. Lineage-tracing analyses showed that Ang II-driven coronary neointima formation occurs beneath an intact endothelial monolayer and is composed predominantly of VSMC-derived cells, highlighting a VSMC-centric vasculopathy distinct from classic endothelium-initiated vascular remodeling. ConclusionHemodynamic pressure overload and AngII-dominant neurohumoral stress drive distinct cardiac remodeling phenotypes: TAC primarily elicits uniform myocardial hypertrophy and interstitial fibrosis, whereas chronic AngII exposure preferentially promotes a VSMC-centric coronary vasculopathy with perivascular fibrosis and elastic lamina injury at lower pressure load. These complementary models help distinguish pressure-dependent from AngII-mediated vascular mechanisms and provide a platform to develop targeted therapies for coronary vasculopathy and AngII-driven vascular disease. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=129 SRC="FIGDIR/small/733633v1_ufig1.gif" ALT="Figure 1"> View larger version (64K): org.highwire.dtl.DTLVardef@469202org.highwire.dtl.DTLVardef@11bde2borg.highwire.dtl.DTLVardef@96ea08org.highwire.dtl.DTLVardef@1deca16_HPS_FORMAT_FIGEXP M_FIG C_FIG

Developmental Biology↗

bioRxiv2026

Stress Granule Coarsening Is a Pathological Inflection Point for Cardiac Electrophysiological Dysfunction

Arrhythmia risk rises early in many forms of cardiac stress, often before contractile failure is evident. Stressed cardiomyocytes accumulate biomolecular condensates, known as stress granules (SGs), whose contribution to this electrical vulnerability has been unclear. We mapped where SGs reside and followed their life cycle under acute and chronic oxidative stress across complementary model systems and assessed electrophysiological consequences with pharmacological tools targeting granule assembly, microtubule integrity, and calcium channel function. Under both stress regimes, SGs localized preferentially to z-lines and intercalated discs, marking these mechanically critical sites as hubs of condensate assembly. Merging of granules, referred to as coarsening, rather than initial formation, emerged as a pathological connection. Early granules were broadly cytoprotective, whereas progressive coarsening was accompanied by disruption of alpha-actinin and L-type calcium channel (Cav1.2) nanodomains and by shortening of action potential (AP) duration. Coarsened granules disorganized Cav1.2 nanodomains through a microtubule-dependent mechanism, and arresting coarsening with nocodazole preserved nanodomain integrity and restored AP morphology. The transition from nascent to coarsened SGs therefore represents a targetable inflection point, and limiting coarsening may prevent proarrhythmic remodeling during cardiac oxidative stress.

bioengineering↗