Abstract 529: Cbfa1 (Runx2) is a Mediator of Aortic Stiffness and Hypertension in a Murine Model of Diabetes Mellitus Type 2

Abstract

Accelerated arterial stiffening is a complication of diabetes mellitus and associated with the development of hypertension. Arterial stiffening results from extensive extracellular matrix remodeling (elastin breakdown, collagen accumulation). The osteogenic transcription factor Cbfa1 (Runx2) has been identified as a mediator of aortic calcification and regulator of matrix protein expression. However, its impact on aortic stiffness is unclear. This study was designed to elucidate the temporal relation between aortic stiffening and the development of arterial hypertension in a murine model of diabetes mellitus type 2. Moreover we aimed to investigate the role of Cbfa1 as potential mediator diabetic aortic stiffening. Serial ex vivo mechanical testing of the thoracic aorta and volume-pressure recording (VPR) based tail-cuff blood pressure measurements revealed that aortic stiffening precedes blood (pulse) pressure elevations in diabetic db/db mice. Vascular stiffening was accompanied by increased medial collagen deposition Picrosirius Red staining). qRT-PCR and immunohistochemistry revealed enhanced expression of Cbfa1 and target genes (Col1a1, Col1a2, FN1, Spp1) in db/db mice compared to controls. Moreover, overexpression of Cbfa1 in vascular smooth muscle (Cbfa1-smTg mice) results in increased medial collagen deposition, aortic stiffness and augmented pulse pressure. Interestingly, Cbfa1-smTg mice did not exhibit enhanced vascular calcification (by von Kossa and Alizarin Red staining). In conclusion we demonstrated that aortic stiffening precedes the onset of hypertension in db/db mice and identified Cbfa1 as mediator of aortic stiffening - presumably via pro-fibrotic mechanisms.