Our goal was to test the hypothesis that cytotrophoblasts, under low oxygen tension, release substances that affect vascular behavior.We studied the vascular response to the vasoconstrictors phenylephrine (receptor dependent) and potassium (receptor independent), the relaxation response to methacholine, and the vasomotor behavior of isolated resistance (mesenteric) arteries from early pregnant rats after incubation in conditioned medium from first-trimester cytotrophoblasts, maintained in standard or hypoxic (2%; 14 mm Hg) culture conditions.After incubation in medium from hypoxic cytotrophoblasts, arterial segments were more responsive to phenylephrine and to potassium-induced constriction but were less responsive to methacholine, and the vasomotor activity was increased compared with that found in vessels incubated in control medium.These changes in vascular behavior are similar to those reported in isolated arteries from women with preeclampsia. These studies provide evidence which suggests that the link between abnormal placentation and maternal vascular abnormality in preeclampsia is the elaboration of vasoactive factors by cytotrophoblasts in response to hypoxia.