ABSTRACT The coronavirus disease 2019 (COVID-19) is a global healthcare crisis that in the USA kills about 1 person every minute. It is caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). While respiratory failure is still the most common cause of mortality in COVID-19 patients, serious manifestations are seen across multiple organs, including the pancreas. There is an intricate relationship between COVID-19 and pancreatic diseases such as pancreatitis and diabetes. Understanding the pathophysiological mechanisms that lead to pancreatic dysfunction and glucose intolerance in infected patients is of utmost importance. The pathogenesis of diabetes is intimately associated with the dysfunction of the pancreatic islet. There are numerous studies indicating that SARS-CoV-2 directly attacks the vascular system. However, the possibility that islet microvascular dysfunction triggers loss of glucose homeostasis in COVID-19 patients has not been explored. This project focuses on the vascular pericyte because our published and preliminary data show that (a) pericytes in human islets are very responsive to angiotensin II and express the key host cellular receptor of SARS-CoV-2, ACE2; (b) pericytes can be infected with SARS-CoV-2 pseudo-entry viruses; and (c) incubation with a SARS-CoV-2 Spike recombinant protein increases pericyte basal Ca2+ levels. We therefore hypothesize that SARS-CoV-2 infects pancreas pericytes, interfering with their contractile properties and impairing their function. Pericyte dysfunction will decrease local blood flow, leading to tissue hypoxia and inflammation and compromising endocrine cell activity. We will test this hypothesis using living pancreas slices from humans and hamsters which are a suitable animal model for COVID-19 research given the high homology of their ACE2 protein sequences. This hypothesis will be tested in two Aims: 1) determine if pericytes are cellular targets of SARS-CoV-2 in the pancreas, and (2) examine the effects of SARS-CoV-2 on islet pericyte function and microvascular responses ex vivo and in vivo. In Aim 1, we will search for SARS-CoV-2 viral particles, characterize microvascular lesions and the pericyte phenotype in the pancreas of COVID-19 patients. We will infect living pancreas slices with SARS-CoV-2 pseudo-entry and live viruses and determine if pericytes are permissive for infection. In Aim 2, we will assess the functional consequences of manipulating ACE2 expression and activity through interactions with SARS-CoV-2 spike protein on pericyte Ca2+ responses and vasomotion ex vivo in living pancreas slices, and in vivo by intraductal injections of pseudo-entry viruses in the hamster pancreas. We will follow longitudinally the effects on glucose metabolism, as well as changes in local hypoxia, inflammation, endocrine cell mass and function. This research has the potential to identify a mechanism of dysfunction in the endocrine pancreas. If the hypothesis is correct, pericyte...