Andrade Barboza Catarina, Gonçalves Luciana Mateus, Pereira Elizabeth, Cruz Roxana Diaz, Andrade Louzada Ruy, Boulina Maria, Almaça Joana
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL.
Department of Physiology and Biophysics, University of Miami Miller School of Medicine, Miami, FL.
Diabetes. 2025 Mar 1;74(3):355-367. doi: 10.2337/db24-0816.
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.
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.
新冠疫情对人类健康产生了深远影响；然而，其对代谢和血管系统影响的潜在机制仍未完全明确。临床证据表明，严重急性呼吸综合征冠状病毒2（SARS-CoV-2）直接破坏血管稳态，在各种组织中观察到灌注异常。胰岛作为一个关键的内分泌小器官，依赖其微血管实现最佳功能，可能特别脆弱。研究提出了SARS-CoV-2感染与胰岛功能障碍之间的联系，但机制尚不清楚。在此，我们研究了SARS-CoV-2刺突S1蛋白如何影响人胰岛微血管功能。利用共聚焦显微镜和来自无糖尿病器官供体的活体胰腺切片，我们发现SARS-CoV-2刺突S1重组蛋白激活周细胞，周细胞是胰岛毛细血管直径和β细胞功能的关键调节因子，并诱导毛细血管收缩。这些效应是由周细胞质膜上血管紧张素转换酶2（ACE2）的丧失驱动的，损害了ACE2活性并增加了局部血管紧张素II水平。我们的研究结果突出了胰岛周细胞功能障碍是SARS-CoV-2致糖尿病作用的一个潜在因素，并为连接新冠疫情、血管功能障碍和糖尿病的机制提供了新见解。
肾素-血管紧张素系统的不同组分在人胰岛的血管细胞中表达。胰岛微血管对血管活性血管紧张素肽有反应。该胰腺肾素-血管紧张素系统在与SARS-CoV-2刺突重组蛋白孵育后成为靶点。SARS-CoV-2刺突激活人胰岛中的周细胞并收缩毛细血管。胰岛血管功能障碍可能导致一些新冠患者出现血糖异常。
