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(Circulation Research. 2007;101:1300.)
© 2007 American Heart Association, Inc.

Integrative Physiology

Propagated Endothelial Ca²⁺ Waves and Arteriolar Dilation In Vivo

Measurements in Cx40^BAC–GCaMP2 Transgenic Mice

Yvonne N. Tallini^*, Johan Fredrik Brekke^*, Bo Shui^*, Robert Doran, Seong-min Hwang, Junichi Nakai, Guy Salama, Steven S. Segal, Michael I. Kotlikoff

From the Biomedical Sciences Department (Y.N.T., B.S., R.D., M.I.K.), College of Veterinary Medicine, Cornell University, Ithaca, NY; the John B. Pierce Laboratory (J.F.B., S.S.S.), Department of Cellular and Molecular Physiology (J.F.B., S.S.S.), Yale University School of Medicine, New Haven, Conn; Cell Biology and Physiology (S.H., G.S.), University of Pittsburgh School of Medicine, Pa; the Laboratory for Memory and Learning (J.N.), RIKEN Brain Science Institute, Hirosawa, Wako-shi, Saitama, Japan; the Department of Medical Pharmacology and Physiology (S.S.S.), University of Missouri, Columbia; and the Dalton Cardiovascular Research Center (S.S.S.), Columbia, Mo.

Correspondence to Dr Michael I. Kotlikoff, Austin O. Hooey Dean, Professor, Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, 2005 Schurman Hall, Ithaca, NY 14853-640. E-mail mik7{at}cornell.edu

To study endothelial cell (EC)– specific Ca²⁺ signaling in vivo we engineered transgenic mice in which the Ca²⁺ sensor GCaMP2 is placed under control of endogenous connexin40 (Cx40) transcription regulatory elements within a bacterial artificial chromosome (BAC), resulting in high sensor expression in arterial ECs, atrial myocytes, and cardiac Purkinje fibers. High signal/noise Ca²⁺ signals were obtained in Cx40^BAC-GCaMP2 mice within the ventricular Purkinje cell network in vitro and in ECs of cremaster muscle arterioles in vivo. Microiontophoresis of acetylcholine (ACh) onto arterioles triggered a transient increase in EC Ca²⁺ fluorescence that propagated along the arteriole with an initial velocity of 116 µm/s (n=28) and decayed over distances up to 974 µm. The local rise in EC Ca²⁺ was followed (delay, 830±60 ms; n=8) by vasodilation that conducted rapidly (mm/s), bidirectionally, and into branches for distances exceeding 1 mm. At intermediate distances (300 to 600 µm), rapidly-conducted vasodilation occurred without changing EC Ca²⁺, and additional dilation occurred after arrival of a Ca²⁺ wave. In contrast, focal delivery of sodium nitroprusside evoked similar local dilations without Ca²⁺ signaling or conduction. We conclude that in vivo responses to ACh in arterioles consists of 2 phases: (1) a rapidly-conducted vasodilation initiated by a local rise in EC Ca²⁺ but independent of EC Ca²⁺ signaling at remote sites; and (2) a slower complementary dilation associated with a Ca²⁺ wave that propagates along the endothelium.

Key Words: bacterial artificial chromosome • calcium imaging • microcirculation • Purkinje cells

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