Endothelium has recently emerged as a therapeutic target in hypertension treatment in that endothelial dysfunction leads to microvascular rarefaction, then target organ damages and cardiovascular disorders in hypertension. It led us to speculate that the angiogenic growth factor, cartilage oligomeric matrix protein-angiopoietin1 (Comp-Ang1), might be a novel class of antihypertensive agents by improving endothelial integrity and function, subsequently attenuating rarefaction and target organ damages. In the experiment with spontaneously hypertensive rats (SHR), we found that electroporation-mediated gene transfer of Comp-Ang1 substantially reduced microvascular rarefaction and organ damage in kidney and heart, as well as significantly lowered the blood pressure in comparison with reporter gene-transferred and untreated SHR. Such an antihypertensive effect of Comp-Ang1 was found to be attributable to not only its property to produce vasodilating nitric oxide, thereby inhibiting the blood pressure elevation in SHR, but also its ability to prevent endothelial dysfunction through promoting vascularization as shown in mesenteric angiogenesis assay, and its anti-inflammatory action in endothelium exposed to hypertensive stimuli. These results imply that Comp-Ang1 with beneficial effects on both blood pressure and endothelium is expected to prevent or even cure the hypertension-associated rarefaction and target organ damages, bringing greater cardiovascular advantages than other antihypertensive therapies focused only on blood pressure control.