Extracellular Matrix-Derived Biophysical Cues Mediate Interstitial Flow-Induced Sprouting Angiogenesis
Extracellular Matrix-Derived Biophysical Cues Mediate Interstitial Flow-Induced Sprouting Angiogenesis
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DOI：
10.1021/acsami.2c15180
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发表时间：
2023-03-14
影响因子：
9.5
通讯作者：
Song，Jonathan W.
中科院分区：
文献类型：
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作者：
Chang，Chia-Wen;Shih，Hsiu-Chen;Song，Jonathan W.
萌发的血管生成是由局部组织微环境中复杂的生化和机械信号的平衡所协调的。间质血流已被证实是血管生成的有效调节因子。同样，细胞外基质(ECM)的物理性质，如硬度和微结构，也成为血管生成的重要介质。然而，间质血流和ECM物理特性在血管生成的启动和控制中的相互作用还知之甚少。使用三维(3D)微流控组织模拟血管生成的发芽，将明确的间质流动叠加在具有良好物理特性的ECM上，我们发现在胶原基质中添加透明质酸(HA)显著增强了间质流动诱导的发芽，而不是单纯胶原水凝胶的反应。我们证实，HA的加入增加了纯胶原水凝胶的硬度和基质孔径。有趣的是，当功能性地阻断HA受体CD44时，间质流动增强的胶原/HA基质中的发芽反应不受影响。相反，含有透明质酸酶(HAdase)的胶原/HA基质中HA的酶促耗竭导致硬度、孔径和间质流动介导的发芽减少到仅有胶原基质中观察到的水平。综上所述，这些结果表明，HA通过改变胶原ECM的硬度和孔大小来增强间质血流介导的血管生成。
Sprouting angiogenesis is orchestrated by an intricate balance of biochemical and mechanical cues in the local tissue microenvironment. Interstitial flow has been established as a potent regulator of angiogenesis. Similarly, extracellular matrix (ECM) physical properties, such as stiffness and microarchitecture, have also emerged as important mediators of angiogenesis. However, the interplay between interstitial flow and ECM physical properties in the initiation and control of angiogenesis is poorly understood. Using a three-dimensional (3D) microfluidic tissue analogue of angiogenic sprouting with defined interstitial flow superimposed over ECM with well-characterized physical properties, we found that the addition of hyaluronan (HA) to collagen-based matrices significantly enhances sprouting induced by interstitial flow compared to responses in collagen-only hydrogels. We confirmed that both the stiffness and matrix pore size of collagen-only hydrogels were increased by the addition of HA. Interestingly, interstitial flow-potentiated sprouting responses in collagen/HA matrices were not affected when functionally blocking the HA receptor CD44. In contrast, enzymatic depletion of HA in collagen/HA matrices with hyaluronidase (HAdase) resulted in decreased stiffness, pore size, and interstitial flow-mediated sprouting to the levels observed in collagen-only matrices. Taken together, these results suggest that HA enhances interstitial flow-mediated angiogenic sprouting through its alterations to collagen ECM stiffness and pore size.