Project Summary/Abstract Despite robust evidence that metabolic syndrome (MetS) is associated with an increased risk of cardiovascular disease (CVD), the mechanism of this increased risk remains obscure. In particular, obesity, hypertension, and diabetes (all components of MetS) have been reported in this population as primary risk factors for cardiac events with the leading cause of mortality. Although the molecular mechanisms underlying abnormal cardiovascular function have been investigated in in-vitro and rodent models under MetS conditions, their exact role in the formation of cardiac collateral vessels is largely unknown. There is a lack of evidence and extension in experiments with large animals and patients of these principles. This awareness is an essential prerequisite for their human application. We will induce MetS with insulin resistance in male intact Yorkshire pigs with high fat feeding a model that recreates many of the metabolic, molecular, and microcirculatory abnormalities present in MetS patients. Our prior studies and preliminary data show that porcine models of diabetes closely resemble the disease in patients and lead to diminish myocardial and vascular regeneration and we will use the model in this proposal. In order to adjust the blood glucose level, we will treat pigs with sitagliptin and canagliflozin and compare the answer to lean diet controls. In this proposal we will concentrate on the effects of SGLT1 inhibition on collateral development and the metabolic, molecular, and microcirculatory abnormalities present in patients with overt diabetes and metabolic syndrome. Our focus is on functional changes in collateral dependent myocardial perfusion, vascular density, and microvascular function together with key molecular events involved in the altered collateral formation process in vivo. We will use mechanistic approach to understand molecular interactions in pathways and networks and functional attributes to unravel the molecular base of impaired angiogenesis in diabetes. Our published and preliminary data suggests for involvement and functional interactions in the hexosamine biosynthetic pathway (HBP), citric acid cycle (CAC), insulin signaling, and protein O-GlcNAcylation. The proposed integrated approach will result in the identification of crucial pathways, molecular targets, and strategies in pro-angiogenic therapy and cell-based regeneration and tissue engineering, the clinical importance of this proposal is evident. The use of a large animal model with type 2 diabetes and metabolic syndrome is a strong aspect of the project.