Background: Chronic hyperhomocysteinemia (HHcy) is an important factor in development of arterial hypertension. HHcy is associated with activation of matrix metalloproteinases (MMPs), however, it is unclear whether HHcy-dependent extracellular matrix (ECM) accumulation plays role in arterial hypertrophy and hypertension. We tested the hypothesis that in HHcy, the mechanism of arterial hypertension involves arterial dysfunction in response to ECM accumulation between endothelial and arterial smooth muscle cells and subsequent endothelium-myocyte (E-M) uncoupling. Methods: To decrease plasma Hcy, dietary supplementation with 3-deaza-adenosine (DZA), the S-adenosyl homocysteine hydrolase (SAHH) inhibitor, was administered to cystathionine synthase (CBS) knockout (KO) mice. Study was done in mice grouped as follows: Wild type (WT, control); WT+DZA; CBSKO; and CBSKO+DZA (n=4 in each group). Mean aortic blood pressure and heart rate were monitored in real time by telemetric system before, during and after DZA treatment (6 wks total). In vivo aorta function and morphology were analyzed by M-mode and Doppler echocardiography in anesthetized mice. Aorta MMPs activity in unfixed cryostat sections was measured by using DQ-gelatin. Expression of aorta MMPs and Connexin-43 were measured by RT-PCR and Western blot analyses, respectively. Results: HHcy caused an increase in aortic blood pressure and resistance; tachycardia; increase in wall thickness and ECM accumulation in aortic wall in comparison to control groups. There was a linear correlation between aortic wall thickness and plasma Hcy levels. MMP-2, -9 and connexin-43 expression were increased in HHcy. Conclusion: The results show that arterial hypertension in HHcy mice is, in part, associated with arterial remodeling and E-m uncoupling in response to MMPs activation. In CBSKO+DZA group, aortic blood pressure, levels of MMP and connexin-43 were close to those found in control groups. However, removal of DZA reversed the aortic lumen/wall thickness to CBSKO, suggesting, in part, a role of vascular remodeling in increase in blood pressure in HHcy. Conclusion: