Pericyte coverage of cardiac capillaries is decreased in diabetic obese mice

Abstract

Heart failure with preserved ejection fraction (HFpEF) which results from diastolic dysfunction is a growing epidemiologic problem. The pathophysiology of this disease is poorly understood nevertheless a theory suggests a central role of microvessel disease. Our goal is to investigate the role of pericyte in the pathophysiology of cardiac microvessel disease and diastolic dysfunction. Pericytes are mural cells known to be essential for microvascular integrity especially in the brain, and in the retina. We have used Leptin receptor deficient (Leprdb/db) female mice as a model of HFpEF and assessed pericyte coverage of cardiac capillaries. Besides, to identify factors that may cause pericyte loss in the heart, we performed, cell viability assays using cultured human pericytes from placenta. In Leprdb/db mice, end-diastolic pressure (EDP) signing diastolic dysfunction is significantly increased from 3 month of age [12.0 ± 1.4 vs 4.4 ± 0.4 mmHg ( P < 0.001)]. It is correlated with signs of microvessel disease especially vascular leakage and endothelial cell activation. Interestingly, we found that pericyte coverage of cardiac capillaries is significantly reduced in Leprdb/db female mice from 6 weeks of age [93.88 ± 2.30 vs 54.67 ± 5.32 ( P < 0.001)]. Notably, this anomaly precedes the onset of endothelial dysfunction and diastolic dysfunction. Cell culture assay showed that oxidized LDLs but not high glucose or TNFα significantly decrease pericyte survival [100.00 ± 6.48 vs 76.22 ± 4.49 with 30 μg/mL ( P < 0.01)]. Our results show that pericyte coverage of capillaries is significantly decreased in the heart of diabetic obese mice probably because of increased oxidized LDL and support that degeneration of cardiac pericytes may contribute to the development of cardiac microvessel disease and diastolic dysfunction in diabetic obese mice and may be due to oxidized LDL.