BRITE Relaunch: Examining the Role of Mechanotransduction in Smooth Muscle Cell Phenotype Modulation

该奖项的全部或部分资金来自《2021年美国救援计划法案》(公共法律117-2)。构成动脉一层的血管平滑肌细胞(VSMCs)表现出两种截然不同的类型：收缩和合成。收缩的VSMCs通过收缩或松弛来调节动脉中的血压。然而，它们可以回复到合成类型，以应对血管损伤。合成的VSMCs负责合成替代细胞和分泌血管愈合所需的物质。这一促进工程转型和公平进展的研究思路(BRITE)重新启动项目假设存在第三种类型的VSMC，并且细胞向这第三种类型的变化是由血管组织内的拉伸引起的。进一步假设，这种向第三种类型的VSMC的变化是通过一种称为Wnt的信号通路发生的。通过这一途径，VSMCs变成骨样细胞，并将矿物质(钙)沉积到细胞周围的动脉组织中，即细胞外基质。导致这种潜在的第三种表型的机械变化是由高血压引起的，高血压被称为沉默的杀手。通过了解与VSMCs行为改变相关的信号通路，可以支持未来的研究，在细胞和分子水平上开发靶向疗法来治疗血管钙化(即动脉硬化)。这项工作可能会推动未来的研究，降低患者经历的心脏病并发症的严重程度，并降低治疗高危患者的成本。该项目还将增加来自代表性不足群体的学生--特别是第一代低收入学生--的研究参与。这个项目将通过研究一种假说来推进知识，即VSMCs对第三种表型的持续可塑性是由机械应变激活典型的Wnt信号通路引起的。体外血管钙化模型将被用来检测机械转导在VSMC表型变化中的作用。该项目将：1)研究合成的VSMC中Wnt信号通路的激活；2)检测表面力学对通过Wnt信号通路激活表型调节的影响；3)检测机械应变下VSMC的表型调节。这种机械负荷将模拟由于高血压引起的血管平滑肌细胞的生理拉伸增加，然后假设这会导致组织内的反应，通过钙化增加其硬度，并将应变范围恢复到组织特定的动态平衡水平。这种机械转导反应已知发生在大多数生物组织中，包括在骨骼中。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

This award is funded in whole or in part under the American Rescue Plan Act of 2021 (Public Law 117-2).The vascular smooth muscle cells (VSMCs) that make up one of the layers of arteries exhibit two distinct types: contractile and synthetic. Contractile VSMCs regulate blood pressure in the artery by contracting or relaxing. However, they can revert into the synthetic type in response to an injury to the blood vessel. Synthetic VSMCs are responsible for synthesis of replacement cells and secretion of substances that are needed for vessel healing. This Boosting Research Ideas for Transformative and Equitable Advances in Engineering (BRITE) Relaunch project has hypothesizes that a third type of VSMCs exists, and the change in the cells to this third type is caused by stretch within the vascular tissue. It is further hypothesized that this change to the third type of VSMC happens through a signaling pathway known as Wnt. Through this pathway, the VSMCs become bone-like cells and deposit mineral (calcium) into the arterial tissue that surrounds the cells, the extracellular matrix. The mechanical changes leading to this potential third phenotype are caused by hypertension, known as the silent killer. By understanding the signaling pathway associated with this change in the behavior of VSMCs, future research can be supported to develop targeted therapeutics to treat vascular calcification (i.e., hardening of the arteries) at the cellular and molecular level. This work could drive future research that will reduce the severity of heart disease complications experienced by patients and reduce the costs of treating high-risk patients. This project will also increase the participation of students from underrepresented groups in research -- in particular, first-generation, low-income students. This project will advance knowledge by investigating the hypothesis that the continued plasticity of VSMCs to a third phenotype is caused by mechanical strain activating the canonical Wnt signaling pathway. An in vitro vascular calcification model will be used to examine the role of mechanotransduction in VSMC phenotype changes. This project will: 1) investigate the activation of a Wnt signaling pathway in synthetic VSMCs; 2) examine the impact of surface mechanics on the activation of phenotypic modulation via the Wnt signaling pathway; and 3) examine the phenotypic modulation of VSMCs under mechanical strain. This mechanical loading will mimic the physiological exposure of VSMCs to increased stretch due to hypertension, which is then hypothesized to cause a response within the tissue to increase its stiffness through calcification and return the range of strains to a tissue-specific homeostatic level. This mechanical transduction response is known to occur in most biological tissues, including in bone.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.