Genetic Dissection of the Vav2-Rac1 Signaling Axis in Vascular Smooth Muscle Cells

Abstract

e 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.

p115 RhoGEF activates the Rac1 GTPase signaling cascade in MCP1 chemokine–induced vascular smooth muscle cell migration and proliferation

“…However, our findings indicate that the p115 RhoGEF, without any effect on RhoA, mediates MCP1-induced Rac1 activation. Rac1 plays a central role in stress fiber formation, and many reports have shown its requirement for both cell migration and proliferation (37)(38)(39). In line with these observations, we have reported previously that activation of Rac1 is required for MCP1-induced HASMC stress fiber formation, migration, and proliferation (20).…”

Targeting of Rac1 prevents bronchoconstriction and airway hyperresponsiveness

“…However, the specific depletion of Rac1 expression in vascular SMCs demonstrates that the activation of Rac1 promotes vasorelaxation by positively regulating cyclic guanosine monophosphate-dependent signaling. 11,12 Inconsistent observations have also been reported in airway SMCs because relaxing properties have been ascribed to Rac1 activity in guinea pig trachea, 24 while activation of Pak1, the main effector of Rac1, has been associated with contraction of murine tracheal segments and human bronchial rings. 14 These results suggest that the regulation of Rac1 activity by contracting agonists, its downstream target effectors, and consequently its functions in the regulation of SMC contraction could be different according to SMC type and/or species.…”

“…9 As intracellular signaling molecules activated by extracellular stimuli, small GTPases of the Rho family (RhoA, Rac1, and Cdc42) act as molecular switches that regulate signaling cascades controlling SMC functions. 10 Increasing evidence implicates the Rho protein Rac1 in the regulation of vascular SMC contraction, 11,12 and genetic deletion of Rac1 regulator 13 or effector 14 has been shown to modulate AHR in experimental allergic models. Furthermore, Rac1 has been identified last year as a potential link between pulmonary inflammation and bronchoconstriction.…”

Vav family exchange factors: an integrated regulatory and functional view

“… 70 This will actually represent a common problem for most Rac1-based therapies, because the inducible smooth muscle cell-specific inactivation of the Rac1 gene in adult mice triggers the same defects. 150, 151 However, these side effects can be prevented, or cured if already developed, using standard anti-hypertensive treatments currently available in the clinic 70,78,82 (S. Fabbiano and X.R.B., manuscript submitted). The systemic inhibition of Vav proteins will also lead to immunosuppression and, possibly, minor defects in other haematopoietic lineages.…”