Franca Cristiane M, Lima Verde Maria Elisa, Silva-Sousa Alice Correa, Mansoorifar Amin, Athirasala Avathamsa, Subbiah Ramesh, Tahayeri Anthony, Sousa Mauricio, Fraga May Anny, Visalakshan Rahul M, Doe Aaron, Beadle Keith, Finley McKenna, Dimitriadis Emilios, Bays Jennifer, Uroz Marina, Yamada Kenneth M, Chen Christopher, Bertassoni Luiz E
Knight Cancer Precision Biofabrication Hub, Knight Cancer Institute, OHSU, Portland, OR 97201, USA.
Cancer Early Detection Advanced Research Center (CEDAR), Knight Cancer Institute, OHSU, Portland, OR 97201, USA.
Sci Adv. 2025 Jan 10;11(2):eadp3789. doi: 10.1126/sciadv.adp3789.
A hallmark of chronic and inflammatory diseases is the formation of a fibrotic and stiff extracellular matrix (ECM), typically associated with abnormal, leaky microvascular capillaries. Mechanisms explaining how the microvasculature responds to ECM alterations remain unknown. Here, we used a microphysiological model of capillaries on a chip mimicking the characteristics of healthy or fibrotic collagen to test the hypothesis that perivascular cells mediate the response of vascular capillaries to mechanical and structural changes in the human ECM. Capillaries engineered in altered fibrotic collagen had abnormal migration of perivascular cells, reduced pericyte differentiation, increased leakage, and higher regulation of inflammatory/remodeling genes, all regulated via , a known mediator of endothelial-perivascular cell communication. Capillaries engineered either with endothelial cells alone or with perivascular cells silenced for expression showed a minimal response to ECM alterations. These findings reveal a previously unknown mechanism of vascular response to changes in the ECM in health and disease.
慢性和炎症性疾病的一个标志是形成纤维化且僵硬的细胞外基质（ECM），这通常与异常、渗漏的微血管毛细血管相关。解释微血管如何响应ECM改变的机制仍然未知。在这里，我们使用了一种芯片上的毛细血管微生理模型，该模型模拟健康或纤维化胶原蛋白的特征，以检验以下假设：血管周围细胞介导血管毛细血管对人ECM中机械和结构变化的反应。在改变的纤维化胶原蛋白中构建的毛细血管具有血管周围细胞的异常迁移、周细胞分化减少、渗漏增加以及炎症/重塑基因的更高调节，所有这些都通过一种已知的内皮 - 血管周围细胞通讯介质进行调节。单独用内皮细胞构建的毛细血管或使血管周围细胞沉默表达的毛细血管对ECM改变的反应最小。这些发现揭示了健康和疾病状态下血管对ECM变化反应的一种先前未知的机制。
