Vascular calcification is an important clinical disease which increases cardiovascular morbidity and mortality, occurring frequently in both diabetes and in chronic renal failure. Previously considered a passive and chronic degenerative condition of ageing, recently it is understood as an active and complex process, with definite pathophysiology that recapitulates osteogenesis. Vascular calcification usually occurs concomitantly with bone loss and bone remodeling such as in osteoporosis and in renal osteodystrophy. Vascular remodeling is an adaptive response of the vessel to specific stimuli, which participates in pathophysiology of various cardiovascular conditions such as aneurism and dissection, atherosclerosis, vascular stiffness, systemic hypertension and arteriovenous fistula. Focusing on cardiovascular risk factors that are common to both vascular calcification and vascular remodeling, we will investigate the mechanisms and pathways that may connect and explain these conditions together. We hypothesized that ob/ob mice, which are obese and have insulin resistance, demonstrate increased excentric vascular remodeling and vascular calcification response to a calcifying stimulus with Vitamin D3 in vivo compared to C57BL/6 mice. Furthermore, we will assess the role of vascular calcification in excentric vascular remodeling and also the association of these conditions with bone loss and bone architecture in this model. More importantly, we will investigate vascular calcifying proteins gene/protein expression change that may activate vascular remodeling mediators such as metalloproteinases, tissue inhibitors of metalloproteinases and increased oxidative stress that may connect vascular calcification to vascular remodeling mechanisms after Vitamin D3 stimulation in vivo in ob/ob compared to C57BL/6 mice. We will assess the role of MSX2, a potent osteogenic transcription factor, in excentric vascular remodeling and in calcification, through investigating the vascular response in MSX2 siRNA transfected obob and C57BL/6 after Vitamin D3 stimulation in vivo. In conclusion, we will pursue novel mechanisms and potential therapeutic targets, through understanding the pathophysiological relationship between excentric remodeling and vascular calcification in obesity and insulin resistant background.
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