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Endocrinology Vol. 140, No. 3 1301-1309
Copyright © 1999 by The Endocrine Society

ARTICLES

Human Vascular Endothelial Cells Express Oxytocin Receptors1

Marc Thibonnier, Doreen M. Conarty, Judy A. Preston, Christine L. Plesnicher, Raed A. Dweik and Serpil C. Erzurum

Division of Clinical and Molecular Endocrinology, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106-4951; and the Department of Cancer Biology at the Cleveland Clinic Research Institute (S.C.E.), Cleveland, Ohio 44195

Address all correspondence and requests for reprints to: Dr. Marc Thibonnier, Room BRB431, Division of Clinical and Molecular Endocrinology, Department of Medicine, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, Ohio 44106-4951. E-mail: mxt10{at}po.cwru.edu

Pharmacological studies in humans and animals suggest the existence of vascular endothelial vasopressin (AVP)/oxytocin (OT) receptors that mediate a vasodilatory effect. However, the nature of the receptor subtype(s) involved in this vasodilatory response remains controversial, and its coupled intracellular pathways are unknown. Thus, we set out to determine the type and signaling pathways of the AVP/OT receptor(s) expressed in human vascular endothelial cells (ECs).

Saturation binding experiments with purified membranes of primary cultures of ECs from human umbilical vein (HUVEC), aorta (HAEC), and pulmonary artery (HPAEC) and [3H]AVP or [3H]OT revealed the existence of specific binding sites with a greater affinity for OT than AVP (Kd = 1.75 vs. 16.58 nM). Competition binding experiments in intact HUVECs (ECV304 cell line) with the AVP antagonist [125I]4-hydroxyphenacetyl-D-Tyr(Me)-Phe-Gln-Asn-Arg-Pro-Arg-NH2 or the OT antagonist [125I]D(CH2)5[O-Me-Tyr-Thr-Orn-Tyr-NH2]vasotocin, and various AVP/OT analogs confirmed the existence of a single class of surface receptors of the classical OT subtype.

RT-PCR experiments with total RNA extracted from HUVEC, HAEC, and HPAEC and specific primers for the human V1 vascular, V2 renal, V3 pituitary, and OT receptors amplified the OT receptor sequence only. No new receptor subtype could be amplified when using degenerate primers. DNA sequencing of the coding region of the human EC OT receptor revealed a nucleotide sequence 100% homologous to that of the uterine OT receptor reported previously.

Stimulation of ECs by OT produced mobilization of intracellular calcium and the release of nitric oxide that was prevented by chelation of extra- and intracellular calcium. No stimulation of cAMP or PG production was noted. Finally, OT stimulation of ECs led to a calcium- and protein kinase C-dependent cellular proliferation response.

Thus, human vascular ECs express OT receptors that are structurally identical to the uterine and mammary OT receptors. These endothelial OT receptors produce a calcium-dependent vasodilatory response via stimulation of the nitric oxide pathway and have a trophic action.




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