SARS-CoV-2 Spike S1 Subunit Triggers Pericyte and Microvascular Dysfunction in Human Pancreatic Islets.

UNLABELLED: The COVID-19 pandemic has profoundly affected human health; however, the mechanisms underlying its impact on metabolic and vascular systems remain incompletely understood. Clinical evidence suggests that SARS-CoV-2 directly disrupts vascular homeostasis, with perfusion abnormalities observed in various tissues. The pancreatic islet, a key endocrine miniorgan reliant on its microvasculature for optimal function, may be particularly vulnerable. Studies have proposed a link between SARS-CoV-2 infection and islet dysfunction, but the mechanisms remain unclear. Here, we investigated how SARS-CoV-2 spike S1 protein affects human islet microvascular function. Using confocal microscopy and living pancreas slices from organ donors without diabetes, we show that a SARS-CoV-2 spike S1 recombinant protein activates pericytes, key regulators of islet capillary diameter and β-cell function, and induces capillary constriction. These effects are driven by a loss of ACE2 from pericytes' plasma membrane, impairing ACE2 activity and increasing local angiotensin II levels. Our findings highlight islet pericyte dysfunction as a potential contributor to the diabetogenic effects of SARS-CoV-2 and offer new insights into the mechanisms linking COVID-19, vascular dysfunction, and diabetes.

ARTICLE HIGHLIGHTS: Different components of the renin-angiotensin system are expressed by vascular cells in human pancreatic islets. The islet microvasculature is responsive to vasoactive angiotensin peptides. This pancreatic renin-angiotensin system is targeted upon incubation with a SARS-CoV-2 spike recombinant protein. SARS-CoV-2 spike activates pericytes and constricts capillaries in human islets. Islet vascular dysfunction could contribute to dysglycemia in some patients with COVID-19.