The role of angiotensin II and FGF interplay in VSMC plasticity in HFpEF

Introduction: Heart failure (HF) with preserved ejection fraction (HFpEF) constitutes ~50% of all heart HF and confers substantial morbidity and mortality in older adults and patients with multiple metabolic comorbidities (Ge, 2020). The pathophysiology of HFpEF is incompletely understood and may go unnoticed at initial stages of its clinical course leading to delayed diagnosis and therapeutic intervention (Shah et al., 2014). The presence of multiple etiologies may be one of the primary factors contributing to the neutral outcomes observed in randomized controlled clinical trials targeting the treatment of HFpEF. To overcome this unsatisfactory situation, an alternative etiology-oriented classification of HFpEF patients could allow stratification into groups that could differentially respond to various treatments (Sidney et al., 2019).Implementing clinical phenotypical classification of HFpEF (Ge, 2020) and correlating it with histological subtypes using animal models of HFpEF has the potential to enhance our understanding of the mechanisms underlying this syndrome and the identification of distinct subgroups of patients that can respond to targeted treatment strategies. Aim: To explore potential mechanisms that regulate vascular remodeling in HFpEF, we hypothesized that inactivation of Fibroblast Growth Factor Receptors ½ in vascular smooth muscle (SM-DCKO) prior to AngII/PE treatment may prevent perivascular fibrosis of coronary arteries Methods Study Design and Model of HFpEF Young (8-10 weeks) male and female WT and SM-DCKO mice were anesthetized with isoflurane. Alzet minipumps were sterilely inserted to allow subcutaneous infusion of Angiotensin II and Phenylephrine for 4 weeks. Mice were randomly selected and assigned into different groups: control mice (either no implantation of any pump or implantation of a pump filled with saline), and mice implanted with an infusion pump with AngII/PE for 28 days. In treatment group osmotic minipumps were programed to deliver either Angiotensin II (1.5 μg/g/day) and Phenylephrine HCl (50 μg/g/day) or double dose of the Angiotensin II (3 μg/g/day). Towards the end of treatment, cardiac function was assessed by echocardiography, and blood pressure was measured with an arterial catheter. Hearts were harvested for histological analysis and biochemical assays. Results: A. Chronic Angiotensin II (1.5 μg/g/day) and Phenylephrine HCl (50 μg/g/day) resulted in interstitial phenotype (55%), perivascular phenotype (30%) and mixed phenotype (15%) based on histological analysis and Mason’s Trichrome staining analysis. B. Chronic double dose Angiotensin II (3 μg/g/day) results in a predominantly perivascular histological HFpEF phenotype (80%) vs mixed perivascular and interstitial phenotype (20%). C. Chronic double dose Angiotensin II (3 μg/g/day) in mice lacking smooth muscle Fgfr1 and Fgfr2 results in absence of a perivascular histological phenotype Conclusions 1. Perivascular phenotype in AngII/PE model of HFpEF is governed primarily by hormonal mechanisms and depends on concentration of angiotensin 2. By modulating FGFR signaling in smooth muscle, we prevent smooth muscle vascular layer hyperplasia Future Steps • To confirm the signaling pathways that lead to loss of the smooth muscle vascular hyperplasia, we will conduct both bulk and single-cell analysis of the vasculature. • In vitro cell studies will be conducted to assess the impact of FGF and its potential to improve the perivascular phenotype This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.