Electron-dense vesicles were observed in rat vascular endothelium. The purpose of this study was to characterize their content(s), venous-arterial distribution and response to chronic orthostatic stress in extremity vessels. Saphenous and brachial vessels – saphenous vein (SV), saphenous artery (SA), brachial vein, brachial artery – were prepared for electron microscopy to quantitate the vesicle area within the endothelium following immunohistochemical and immunocytochemical identification. The effect of long-term orthostasis was assessed by exposure to head-up tilt for 2 weeks. The vesicular area in relation to the total cross-sectional area of the endothelial cells in the SV and SA of normal and confined control groups was 3.88 ± 0.38 versus 0.89 ± 0.06% (p < 0.05) and 4.92 ± 0.25 versus 1.09 ± 0.47% (p < 0.05), respectively. Head-up tilt suppressed the vesicle content of the SV to 2.26 ± 0.39% (p < 0.05), but it remained low in the SA (1.29 ± 0.45%), brachial vein (0.45 ± 0.12%) and brachial artery (0.59 ± 0.17%). Endothelin and platelet-derived growth factor, but not acidic phosphatase activity or lipid content, could be identified in the vesicles. Plasma endothelin levels were unchanged. We conclude that dense vesicles in the endothelium of extremity vessels are not cell degradation products. They may represent a vesicular secretory or storage system for endothelin and platelet-derived growth factor which participates in regional vascular adaptation to long-term orthostatic load.