The Role of CD44v6 in Vascular Rarefaction and Left Ventricular Diastolic Dysfunction in HFpEF

Abstract

CD44 is differentially spliced to form specific CD44 variants, but little is known regarding their specific contribution to cardiovascular pathologies. Specifically, CD44 variant 6 (CD44v6) is involved in abnormal angiogenesis. The hypothesis tested was that CD44v6 leads to coronary microvascular rarefaction whereby it contributes to left ventricle (LV) diastolic function in heart failure with preserved ejection fraction (HFpEF, also known as diastolic heart failure). The obese ZSF1 rat model of human HFpEF was employed and using transthoracic echocardiography, it was found that 21‐week‐old male obese ZSF1 rats exhibited diastolic dysfunction, accompanied with increased myocardial expression of CD44v6. Coronary arteriolar and capillary trees were labeled using Tomato Lectin (Lycopersicon esculentum) DyLight®594 and were imaged by fluorescent confocal microscopy to generate image stacks for 3D reconstruction. Unbiased automated tracing of the microvasculature was done using VesselLucida360 software (MBF) followed by a morphometric analysis (VesselLucida Explorer). It was found that total vessel length and the number of vessel’s branching nodes were reduced in the obese ZSF1 rats, whereas the total vessel’s volumes remained unchanged, when compared to the lean ZSF1 controls. These changes in the microvasculature were accompanied by decreased angiogenesis in the coronary arteries in the obese ZSF1 rats when compared to the lean ZSF1 rats. From these results, it was concluded that upregulation of CD44v6 plays a role in the impaired angiogenesis underlying the development of LV diastolic dysfunction in HFpEF.