Abstract P380: Common And Distinct Signatures Of Interstitial And Perivascular Fibrosis In Mouse Models Of Hypertensive Heart Disease

Fibrosis is the hallmark of hypertensive heart disease and heart failure with preserved ejection fraction. Perivascular fibrosis impairs vascular function while interstitial fibrosis leads to compromised cardiac contractility. How these fibrosis types are represented in mouse models of hypertensive heart disease and to what extent the transcriptional signatures of cardiac fibrosis are defined by their location is unknown. Mice were dosed over 4 weeks with angiotensin II (AngII) alone or together with α 1 -adrenergic agonist phenylephrine (PE) and were characterized by echocardiography, light sheet imaging and fibrosis histology. While both groups developed systolic and diastolic dysfunction, hypertrophy and perivascular fibrosis, co-administration of PE resulted in a more severe disease phenotype and prevalent interstitial fibrosis, highlighting the benefits of this model in preclinical research. High-precision spatial transcriptomics based on laser capture microdissected perivascular and interstitial fibrotic areas revealed activation of distinct pro-fibrotic as well as cardioprotective pathways in the AngII+PE infusion model. Perivascular and interstitial fibrosis showed remarkable differences in global gene expression signatures, as demonstrated by high expression of osteochondrogenic genes and markers of secretory fibroblasts in perivascular fibrosis. A limited number of upregulated genes is shared between the fibrosis locations. These data collectively show the suitability of mouse models of hypertensive heart disease to study cardiac fibrosis and demonstrate how progression of fibrosis in mice is closely coupled to deteriorating cardiac dysfunction associated with highly distinct molecular signatures of perivascular and interstitial fibrosis.