The cells of the vascular system are highly sensitive to biophysical cues from their local cellular microenvironment. To engineer improved materials for vascular devices and delivery of cell therapies, a key challenge is to understand the mechanisms that cells use to sense biophysical cues from their environment. Syndecans are heparan sulfate proteoglycans (HSPGs) that consist of a protein core modified with heparan sulfate glycosaminoglycan chains. Due to their presence on the cell surface and their interaction with cytoskeletal and focal adhesion associated molecules, cell surface proteoglycans are well poised to serve as mechanosensors of the cellular microenvironment. Nanotopological cues have become recognized as major regulators of cell growth, migration and phenotype. We hypothesized that syndecan-1 could serve as a mechanosensor for nanotopological cues and can mediate the responsiveness of vascular smooth muscle cells to nanoengineered materials. We created engineered substrates made of polyurethane acrylate with nanogrooves using ultraviolet-assisted capillary force lithography. We cultured vascular smooth muscle cells with knockout of syndecan-1 on engineered substrates with varying compliance and nanotopology. We found that knockout of syndecan-1 reduced alignment of vascular smooth muscle cells to the nanogrooves under inflammatory treatments. In addition, we found that loss of syndecan-1 increased nuclear localization of Yap/Taz and phospho-Smad2/3 in response to nanogrooves. Syndecan-1 knockout vascular smooth muscle cells also had elevated levels of Rho-associated protein kinase-1 (Rock1), leading to increased cell stiffness and an enhanced contractile state in the cells. Together, our findings support that syndecan-1 knockout leads to alterations in mechanosensing of nanotopographical cues through alterations of in rho-associated signaling pathways, cell mechanics and mediators of the Hippo and TGF-β signaling pathways.

血管系统的细胞对来自其局部细胞微环境的生物物理线索高度敏感。为了设计出用于血管装置和细胞疗法的改良材料，一项关键的挑战是要了解细胞用来从其环境中感知生物物理线索的机制。Syndecans是硫酸乙酰肝素蛋白聚糖（HSPG），由被硫酸乙酰肝素糖胺聚糖链修饰的蛋白质核心组成。由于它们在细胞表面上的存在以及它们与细胞骨架和粘着斑相关分子的相互作用，因此细胞表面蛋白聚糖有望成为细胞微环境的机械传感器。纳米拓扑线索已被公认为细胞生长，迁移和表型的主要调节因子。我们假设syndecan-1可以用作纳米拓扑线索的机械传感器，并可以介导血管平滑肌细胞对纳米工程材料的响应。我们使用紫外线辅助毛细管力光刻技术，创建了具有纳米凹槽的聚氨酯丙烯酸酯制成的工程基板。我们在具有不同顺应性和纳米拓扑结构的工程化底物上培养了syndecan-1的敲除培养了血管平滑肌细胞。我们发现敲除syndecan-1减少了炎症治疗下血管平滑肌细胞与纳米槽的对齐。此外，我们发现syndecan-1的丢失增加了对纳米槽的响应，Yap / Taz和phospho-Smad2 / 3的核定位。Syndecan-1基因敲除的血管平滑肌细胞中Rho相关蛋白激酶1（Rock1）的水平也升高，导致细胞刚度增加和细胞收缩状态增强。在一起，我们的研究结果支持syndecan-1基因敲除通过改变与rho相关的信号传导途径，细胞机制以及Hippo和TGF-β信号传导途径的介导作用，从而改变了纳米地形线索的机械感测。