Karakaya Cansu, van Turnhout Mark, van den Hurk Eva A N, Bouten Carlijn V C, Sahlgren Cecilia M, Loerakker Sandra
Department of Biomedical Engineering, Eindhoven University of Technology, 5600 MB, Eindhoven, the Netherlands.
Institute for Complex Molecular Systems, Eindhoven University of Technology, 5600 MB, Eindhoven, the Netherlands.
Integr Biol (Camb). 2025 Jan 8;17. doi: 10.1093/intbio/zyaf007.
Vascular smooth muscle cells (VSMCs) play a crucial role in vascular growth and remodeling by adapting their phenotype in response to biomechanical cues. The Notch signaling pathway, known for its sensitivity to mechanical forces, is a regulator of strain-induced phenotypic plasticity of VSMCs. However, the impact of the intricate mechanical environment within the vessel wall on Notch signaling and VSMCs is not completely elucidated. In this study, we investigated the influence of strain anisotropy, which is important for understanding (patho)physiological mechanical conditions, on mechanosensitive Notch signaling and subsequent changes in VSMC phenotype. Using varying amplitudes of cyclic strain in the physiological range, we examined the effects of equibiaxial and uniaxial strain on Notch signaling and phenotypic transitions in synthetic and contractile VSMCs. Additionally, we compared cell responses between equibiaxial and uniaxial loading conditions by analyzing three different deformation characteristics to determine the primary strain measure governing Notch signaling and VSMC phenotype. Our findings reveal that both cyclic equibiaxial and uniaxial strain downregulate Notch signaling and contractile characteristics of VSMCs. Notably, these reductions are most similar for both loading conditions when the maximum principal strain values were compared. Overall, our results suggest that VSMCs respond in a comparable manner to equibiaxial and uniaxial strain, indicating that strain anisotropy may not significantly influence Notch signaling or phenotypic switching of VSMCs. Insight Box: Vascular smooth muscle cells (VSMCs) adapt their phenotype during vascular growth and remodeling in response to mechanical cues. The Notch signaling pathway, sensitive to mechanical stimuli, regulates this phenotypic plasticity. However, the effect of strain anisotropy, which is important for understanding (patho)physiological mechanical conditions, on Notch signaling and subsequent changes in VSMC phenotype is not clear. Understanding this relationship is crucial to determine how VSMC phenotype, contributing to vascular growth and remodeling, is regulated in physiological and pathological hemodynamic environments. Here, we showed that both equibiaxial and uniaxial strain downregulate Notch signaling components and the contractile properties of VSMCs. Our findings further highlighted the maximum principal strain as the dominant mechanical parameter influencing Notch signaling and VSMC phenotypic changes.
血管平滑肌细胞（VSMCs）通过响应生物力学信号改变其表型，在血管生长和重塑过程中发挥着关键作用。Notch信号通路以其对机械力的敏感性而闻名，是血管平滑肌细胞应变诱导表型可塑性的调节因子。然而，血管壁内复杂的机械环境对Notch信号和血管平滑肌细胞的影响尚未完全阐明。在本研究中，我们研究了应变各向异性（这对于理解（病理）生理机械条件很重要）对机械敏感的Notch信号和血管平滑肌细胞表型随后变化的影响。我们使用生理范围内不同幅度的循环应变，研究了等双轴和单轴应变对合成型和收缩型血管平滑肌细胞中Notch信号和表型转变的影响。此外，我们通过分析三种不同的变形特征，比较了等双轴和单轴加载条件下的细胞反应，以确定控制Notch信号和血管平滑肌细胞表型的主要应变指标。我们的研究结果表明，循环等双轴和单轴应变均下调Notch信号和血管平滑肌细胞的收缩特性。值得注意的是，当比较最大主应变值时，两种加载条件下的这些降低最为相似。总体而言，我们的结果表明，血管平滑肌细胞对等双轴和单轴应变的反应方式相似，这表明应变各向异性可能不会显著影响Notch信号或血管平滑肌细胞的表型转换。洞察框：血管平滑肌细胞（VSMCs）在血管生长和重塑过程中响应机械信号改变其表型。对机械刺激敏感的Notch信号通路调节这种表型可塑性。然而，应变各向异性（这对于理解（病理）生理机械条件很重要）对Notch信号和血管平滑肌细胞表型随后变化的影响尚不清楚。了解这种关系对于确定在生理和病理血液动力学环境中，对血管生长和重塑有贡献的血管平滑肌细胞表型是如何被调节至关重要。在这里，我们表明等双轴和单轴应变均下调Notch信号成分和血管平滑肌细胞的收缩特性。我们的研究结果进一步强调了最大主应变是影响Notch信号和血管平滑肌细胞表型变化的主要机械参数。
