CAREER: Trauma-Induced Alteration of Vascular Smooth Muscle Mechanics

爆炸引起的创伤性脑损伤（bTBI）可能发生在暴露于附近爆炸的冲击波后，即使没有可见的损伤。 脑损伤的一个常见后果是大脑动脉周围的小肌肉痉挛，从而切断血液循环。脑血管痉挛在爆炸伤后比在钝力脑损伤后更常见。最近的研究结果表明，当冲击波进入人体时，它会优先通过动脉传播，拉伸和伤害小肌肉，导致痉挛。这个教师早期职业发展（CAREER）计划奖支持基础研究，旨在了解创伤性力量，如bTBI中的创伤性力量，如何改变血管平滑肌细胞的特性和行为。其结果将是更好地了解bTBI损伤的机制，为潜在的治疗方法提供见解。我们最近的研究结果表明，大的高应变率应力在脑血管平滑肌细胞在爆炸可以启动过度收缩和表型转换，这两者都是血管痉挛发作的指标，并可能改变细胞的机械性能。我们假设：（1）在冲击伤期间，当血管平滑肌细胞中的应力超过某一阈值时，可引发脑血管痉挛;和（2）冲击伤引起的过度收缩和表型转换诱导血管平滑肌细胞机械性质的变化，这导致在随后的冲击伤期间更大的细胞应力，增加进一步损伤的可能性。在这里，我们将开发新的方法来测量的各向异性和非线性应变能密度函数和准线性粘弹性性能的个别细胞，以确定在冲击伤过程中的VSMCs的应力。然后，我们将应用爆炸样的高速拉伸VSMC和测量收缩性，表型和机械性能的变化，以确定如何血管痉挛发作影响血管细胞应力在随后的损伤。

Blast-induced traumatic brain injury (bTBI) can occur following exposure to the blast wave from a nearby explosion even in the absence of visible injury. A common consequence of brain injury is a spasm in the small muscles surrounding the arteries of the brain that cuts off circulation. Cerebral vasospasm is more common after a blast injury than after a blunt force brain injury. Recent results suggest that when a blast wave enters the body it travels preferentially through the arteries, stretching and injuring the small muscles and causing the spasm. This Faculty Early Career Development (CAREER) Program award supports fundamental research aimed at understanding how traumatic forces, like those in bTBI, alter the properties and behavior of vascular smooth muscle cells. The result will be a better understanding of the mechanisms involved in bTBI injury, providing insight for potential therapeutic approaches. Our recent findings suggest that large high-strain-rate stresses in cerebral VSMCs during a blast can initiate hypercontractility and phenotype switching, both of which are indicative of vasospasm onset, and are likely to alter the mechanical properties of the cells. We hypothesize that: (1) cerebral vasospasm can be initiated when stress in vascular smooth muscle cells exceeds some threshold value during blast injury; and (2) hypercontractility and phenotype switching caused by blast injury induce changes in vascular smooth muscle cell mechanical properties that result in greater cell stresses during subsequent blasts, increasing the likelihood of further injury. Here, we will develop novel methods for measuring the anisotropic and nonlinear strain energy density function and quasilinear viscoelastic properties of individual cells to determine the stress in VSMCs during blast injury. We will then apply blast-like high-velocity stretching to VSMCs and measure the changes in contractility, phenotype, and mechanical properties to determine how vasospasm onset influences vascular cell stress during subsequent injuries.