Abstract Introduction: Hypertension is a major risk factor for heart disease and stroke. Optimally treated hypertensive patients still have 50% greater cardiovascular risk than untreated normotensive subjects. Despite current medication, half a million deaths in the United States include hypertension as a primary contributing cause in 2018 presenting a need for additional targets. Vascular smooth muscle cells (VSMCs) are the fulcrum of vascular disease, particularly hypertension. VSMCs play an essential role in vascular contractility and the regulation of blood pressure. Fragile X-related protein (FXR1) is a muscle-enhanced RNA binding protein and we previously found siRNA knock down of FXR1 increases inflammatory mRNA stability. Overexpression of FXR1 decreases inflammatory mRNA stability in VSMC. Little is known concerning FXR1 protein binding partners and its role in vascular disease. The specific aim of this study is to test the hypothesis that FXR1 regulates vascular contractility by RNA stability and protein interactions. Results: We generated a novel, VSMC-specific FXR1 conditional knock out mouse (FXR1VSMC/VSMC) in order to establish an in vivo role of FXR1 in vascular disease. Preliminary data indicates that these mice are hypotensive as they show decreased systolic (P < 0.001) and diastolic (P < 0.01) blood pressure , and increased resting heart rate (P < 0.05) at baseline compared to controls. Gene ontology of RNA immuno-precipitation sequencing analysis in human VSMCs identified that FXR1 binds to mRNA that participate in VSMC contractility and regulation of blood pressure- related pathways. Although considered an RNA stability protein, mass- spectrometry identified that FXR1 interacts with proteins related to contractile processes such as cell migration, adhesion and stress fiber formation. siRNA knock down of FXR1 decreased VSMC migration and collagen gel contraction corroborating in vivo observations. Conclusion: These data are the first to suggest FXR1 regulates blood pressure and vascular contractility potentially by two mechanisms: mRNA stability and functional activity by protein-protein interactions. The findings support FXR1 activity may represent a target for therapeutic invention to regulate blood pressure.