This study was planned to obtain ultrastructural details of the early changes in intra-acinar arterioles in acute hypoxic pulmonary hypertension that could lead to understanding the mechanisms in the development of chronic hypoxic hypertension. In the anesthetized rat, using 5-10% normobaric O2, within minutes after hypoxia, there are changes in endothelial cells characteristic of activation: prominence of cell body and protuberance of the nucleus, electron-dense membrane-bound bodies adluminally, increasing pseudopodia of the adluminal cell membrane, edema within (vacuoles) and beneath the endothelial cells with separation of the endothelial cells from the basal lamina. There is activation of platelets and leucocytes in the lumen and accumulation of platelets at the endothelium. Arteriolar wall edema rapidly increases, is excessive within 1 h, with dissection of the basal lamina and wall and cytolysis of wall components. At 24 h edema is reduced, the number of platelets is increased at the endothelium and fibroblasts are newly aligned within the arteriolar wall. At 48 h platelets further increase, a basal lamina develops in fibroblasts termed transitional cells and myofibrils occur subsequently to form smooth muscle. These findings suggest that activation of the endothelial cell is the initial event in a cellular cascade in the arteriolar hypoxic responses with fibroblast-to-smooth muscle transformation, which results in pulmonary arteriolar hyperplasia and vascular remodeling in hypoxic chronic pulmonary hypertension.