Ischemia/Reperfusion injury and Myocardial edema

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Project Summary Uncontrolled inflammation is a key driver of acute and chronic cardiovascular pathology. However, the accompanying edema, one of the four cardinal signs of inflammation defined by Celsus and Galen two millennia ago, is poorly understood and often ignored at the mechanistic level. Yet ample evidence shows its causal roles in ischemia reperfusion injury (IRI) and resultant sequelae in the heart, brain, and other organs. While a number of molecules can induce edema formation, vascular endothelial growth factor (VEGF), also known as vascular permeability factor (VPF) has been viewed as the key component of IRI-associated edema development. There are a number of drugs capable of blocking VEGF signaling, including vascular permeability that are widely used as anti- angiogenic cancer and ophthalmologic drugs such as bevacizumab, sorafenib, sunitinib and pazopanib among others. However, none of them can be used in acute/chronic ischemia settings due to the induced loss of blood vasculature. Exciting new data from our lab have demonstrated that it is possible to selectively block VEGF- induced permeability defects without affecting other aspects of its signaling, thereby eliminating anti-angiogenic effects of non-selective anti-VEGF therapies. In preliminary studies, blocking VEGF-blocking edema formation leads to a ~50% reduction in the size of myocardial infarction and preservation of LV systolic and diastolic function and suppression of VT inducibility. With these preliminary results in hand, we propose to examine the functional effects myocardial edema and evaluate the effect of anti-edema therapies in this setting.