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Background: Arterial hypertension (HT) is a complex multifactorial condition associated with cardiovascular disease. Independent studies show that HT is associated with microcirculatory and hemorheological alterations, such as decreased red blood cell (RBC) deformability, as well as decreased endothelial function and nitric oxide (NO) bioavailability. Recently we found RBC carry an active endothelial nitric oxide synthase (eNOS), which is decreased in cardiovascular disease.Hypothesis: We hypothesized that a reduced RBC deformability may contribute to induce a hypertensive phenotype via impairment of microcirculatory conductance. Methods: To evaluate hemorehological alterations in HT, patients (n =10) with HT and age-and risk factors-matched subjects (n =10) without HT (control) were recruited. High BP was defined as systolic BP>135mmHg and diastolic BP>85mm in 24h BP measurements. RBC deformability was measured by laser-assisted optical rotational cell analyzer (LORCA) and assessed as elongation index (EI) at 1.73Pa. RBC redox state (ROS, GSH) was assessed by labeling with diclorodihydrofluorescein and thiol-tracker and flow cytometry. Cutaneous microvascular function as post-occlusion reactive hyperemia was measured by noninvasive laser Doppler Perfusion imaging and quantified as area under the curve (AUC). Endothelial function of the brachial artery was assessed as flow-mediated dilatation (FMD) by high resolution ultrasound. Deformability of RBC from eNOS−/− mice was evaluated and compared to wild type (WT) C57Bl/6 mice. To evaluate NO and NOS-dependent changes in RBC deformability, RBC from healthy individuals (n =6) were treated with NO donors, NOS inhibitors and guanylate cyclase inhibitors. Measurements of cGMP production in RBC were assessed by ELISA. A stepwise linear regression as well as a multivariate linear regression model were performed to identify independent predictors for systolic BP. Results: In the HT group EI (0.300±0.007 vs. 0.326±0.007, p =0.013), AUC (1657±422 vs. 2313±473 PU; p =0.009). and FMD (6.2%±0.7% vs. 5.0%±0.3 % p =0.010) was reduced in the HT group, suggesting decreased deformability, shorter lasting vasodilation of microvessels and endothelial dysfunction. In RBC from HT patients the ROS levels increased and the GSH levels decreased, indicating increased oxidative stress. Univariate inverse correlations were found between systolic BP and AUC (r =−0.485; p <0.042) and systolic BP and EI (r =0.726; p <0.001). In a multivariate linear regression analysis including EI, AUC, FMD, EI was identified as an independent predictor for systolic BP explaining 61% of the total variability of the systolic blood pressure (adjusted R 2 =0.607, p =0.004). In a translational approach we analyzed deformability in eNOS−/− mice, characterized by a dysfunctional endothelium and hypertension. eNOS−/− RBC are less deformable than WT RBC, show increased ROS and decreased GSH, similarly to the HT grouP Moreover, NO donors increased EI of RBC from healthy individuals, while NOS inhibition as well as guanlyte cyclase inhibition decreased cGMP levels and EI indicating that NO/NOS/cGMP dependent pathways control deformability in RBC. Conclusion: The NO/NOS/cGMP pathway controls RBC mechanoproperties, and RBC deformability is an independent predictor of increased blood pressure in patients with arterial hypertension. Disclosure: Nothing to disclose. [ABSTRACT FROM AUTHOR]