Circulating pro-angiogenic cells are preserved despite myocardial angiogenic signal deficits in HFpEF model

Abstract Heart failure with preserved ejection fraction (HFpEF) has no cure, and microvascular dysfunction is a major contributing factor to its pathophysiology. Circulating endothelial progenitor cells (EPCs) and Angiogenic T (i.e., Tang) cells which support vascular repair are deficient in clinical HFpEF. The lack of data on circulating EPC and Tang cell counts in HFpEF models is an unmet critical gap in knowledge for potential therapeutic and biomarker development for HFpEF. In the clinically relevant HFpEF model (i.e., ZSF-1 obese rats), we hypothesized that circulating EPCs and Tang cell counts are significantly decreased compared to healthy control (WKY) rats. Thirty-eight-week-old male ZSF-1 obese and WKY rats were subjected to comprehensive phenotyping protocol, including echocardiography, exercise tolerance, aortic pressure measurement, and left ventricular diastolic function assessment. Blood was analyzed by flow cytometry for early (CD146⁺/CD34⁺/CD133⁺) and late (CD34⁺/CD146⁺) EPCs, as well as Tang cells (CD3⁺/CXCR4⁺/CD31⁺). Left ventricular expression of angiogenic genes (SDF1α, VEGFα) and pro-inflammatory IL-1β gene was quantified. ZSF-1 obese rats exhibited severe HFpEF phenotype with impaired diastolic function, elevated filling pressures, and significant exercise intolerance. Contrary to our expectations, circulating EPC and Tang cell counts in ZSF-1 obese rats are comparable to those of WKY rats whereas myocardial expression of SDF-1α and VEGF-α were markedly reduced and IL-1β gene increased. These findings suggest a novel dissociation between circulating and tissue angiogenic profiles in HFpEF. Preserved circulating pro-angiogenic cells despite myocardial angiogenic deficits suggests angiogenic dissociation as a potential mechanism underlying microvascular dysfunction in HFpEF. While ZSF-1 lean rats would have been the ideal control instead of WKY, targeting myocardial angiogenic pathways in HFpEF may represent a promising therapeutic strategy.