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(Circulation Research. 2006;98:1203.)
© 2006 American Heart Association, Inc.

Integrative Physiology

Endostatin, the Proteolytic Fragment of Collagen XVIII, Induces Vasorelaxation

D. Wenzel, A. Schmidt, K. Reimann, J. Hescheler, G. Pfitzer, W. Bloch, B.K. Fleischmann

From the Institute of Physiology I (D.W., B.K.F.), University of Bonn; Department of Molecular and Cellular Sport Medicine (A.S., W.B.), German Sport University Cologne; and Institutes of Vegetative Physiology (K.R., G.P.) and Neurophysiology (J.H.), University of Cologne, Germany.

Correspondence to B.K. Fleischmann, MD, Institute of Physiology I, University of Bonn, Argelanderstr. 2a, 53115 Bonn, Germany. E-mail bernd.fleischmann{at}uni-bonn.de

Collagen XVIII is an important component of the extracellular matrix and is expressed in basement membranes. Its degradation results in the generation of endostatin claimed to possess antiangiogenic activity. To date, only limited knowledge exists with regard to the cellular signaling of this molecule. We show in single-cell measurements using the Ca²⁺ indicator fura-2 acetoxy methylester (fura-2 AM) and the nitric oxide (NO) indicator 4,5-diaminofluorescein diacetate that application of endostatin (ES) (5 pmol/L, 100 ng/mL) induced Ca²⁺ spikes and an increase of NO production in human and murine endothelial cells. The NO response was independent of an increase in cytosolic Ca²⁺ and blocked by the endothelial NO synthase (eNOS) inhibitor N^G-nitro-L-arginine methyl ester and by incubation with pertussis toxin known to inhibit G_i/o proteins. The physiological relevance of this novel signaling pathway of ES was assessed with isometric force measurements in large and small arteries of mouse. Physiological concentrations of ES were found to decrease vascular tone in an endothelium-dependent manner. This occurred via an Arg-Gly-Asp (RGD) peptide–independent pathway through activation of G_i/o proteins, phosphatidylinositol 3-kinase, Akt, and eNOS. We conclude that the proteolytic matrix fragment ES is a prominent vasorelaxing agent. Because ES is constantly released into the blood, it is a novel regulator of blood pressure and, therefore, represents an interesting pharmacological target.

Key Words: vascular tone • extracellular matrix • endostatin • nitric oxide • G proteins

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