Centro de Investigación del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC) and University of Salamanca, Campus Unamuno, Salamanca, Spain Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC) and University of Salamanca, Campus Unamuno, Salamanca, Spain.
Departamento de Fisiología y Farmacología, University of Salamanca, Campus Unamuno, Salamanca, Spain.
Mol Cell Biol. 2014 Dec;34(24):4404-19. doi: 10.1128/MCB.01066-14. Epub 2014 Oct 6.
Vascular smooth muscle cells (vSMCs) are key in the regulation of blood pressure and the engagement of vascular pathologies, such as hypertension, arterial remodeling, and neointima formation. The role of the Rac1 GTPase in these cells remains poorly characterized. To clarify this issue, we have utilized genetically engineered mice to manipulate the signaling output of Rac1 in these cells at will using inducible, Cre-loxP-mediated DNA recombination techniques. Here, we show that the expression of an active version of the Rac1 activator Vav2 exclusively in vSMCs leads to hypotension as well as the elimination of the hypertension induced by the systemic loss of wild-type Vav2. Conversely, the specific depletion of Rac1 in vSMCs causes defective nitric oxide vasodilation responses and hypertension. Rac1, but not Vav2, also is important for neointima formation but not for hypertension-driven vascular remodeling. These animals also have allowed us to dismiss etiological connections between hypertension and metabolic disease and, most importantly, identify pathophysiological programs that cooperate in the development and consolidation of hypertensive states caused by local vascular tone dysfunctions. Finally, our results suggest that the therapeutic inhibition of Rac1 will be associated with extensive cardiovascular system-related side effects and identify pharmacological avenues to circumvent them.
血管平滑肌细胞（vSMCs）在调节血压和血管病理方面起着关键作用，如高血压、动脉重塑和新生内膜形成。Rac1 GTPase 在这些细胞中的作用仍未得到充分描述。为了解决这个问题，我们利用基因工程小鼠，通过诱导型 Cre-loxP 介导的 DNA 重组技术，随意操纵 Rac1 在这些细胞中的信号输出。在这里，我们表明，仅在 vSMCs 中表达活性形式的 Rac1 激活因子 Vav2 会导致低血压，以及消除全身性野生型 Vav2 缺失引起的高血压。相反，vSMCs 中 Rac1 的特异性耗竭会导致一氧化氮血管舒张反应缺陷和高血压。Rac1（而不是 Vav2）对于新生内膜形成也很重要，但对于高血压驱动的血管重塑则不重要。这些动物还使我们能够排除高血压和代谢疾病之间的病因联系，最重要的是，确定了在由局部血管张力功能障碍引起的高血压状态的发展和巩固过程中合作的病理生理程序。最后，我们的结果表明，Rac1 的治疗抑制将与广泛的心血管系统相关的副作用相关联，并确定了规避它们的药理学途径。
