100-OR: Investigating the Mechanisms of Cross Talk between Endocrine Beta Cells and Pericytes in Pancreatic Islets

Introduction: Islets are small endocrine organs scattered throughout the exocrine pancreas. Although endocrine and exocrine tissues share their vascular networks, a selective increase in islet blood flow is observed upon increases in glycemia. We showed that pericytes mediate changes in islet blood flow. The aim of this study was to determine whether glucose affects directly islet pericytes or indirectly by changing endocrine cell activity and stimulating the release of vasoactive factors which act on pericytes. Methods: To manipulate (acutely and chronically) endocrine beta cells without changing systemic glycemia, we injected adeno-associated viruses encoding excitatory designer receptors exclusively activated by designer drugs (DREAAD) under the insulin promoter. Also we treated mice with multiple low doses of the beta cell toxin streptozotocin (5 days - 50 mg/kg/day) for 2 weeks, causing only glucose intolerance. We used mice that express a genetically encoded Ca2+i indicator in pericytes to monitor pericyte activity. Results: We found that acute activation of beta cells with the DREAAD agonist clozapine decreased Ca2+i in islet pericytes in vivo (exteriorized pancreas) and ex vivo (living pancreas slices). Blocking adenosine and serotonin receptors with specific receptor antagonists rescued the inhibitory effects of clozapine. Chronic ablation of beta cells with streptozotocin abolished the glucose-dependent decrease in pericyte Ca2+i and dilation of islet capillaries in pancreas slices. Conclusions: Our study indicates that beta cells participate in the acute regulation of islet blood flow. By releasing vasoactive factors, such as adenosine and serotonin, beta cell activation decreases islet pericyte activity which results in capillary dilation and increased blood flow. Endocrine cell dysfunction that occurs during the development of diabetes may affect islet pericyte and vascular responses, impairing hormone release into circulation. Disclosure L. Mateus Goncalves: None. E. Pereira: None. J. Almaca: None. Funding National Institutes of Health (5R01DK133483-02 - J.A.)Helmsley Charitable Trust George Eisenbarth Pilot Award for nPOD team Science (J.A.)2022 Stanley Glaser Award from the University of Miami (J.A.).