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Age-Associated Induction of Cell Membrane CD47 Limits Basal and Temperature-Induced Changes in Cutaneous Blood Flow

Rogers, Natasha M. MD, PhD; Roberts, David D. PhD§; Isenberg, Jeffrey S. MD, MPH*,†,‡

doi: 10.1097/SLA.0b013e31827e52e1
Original Articles

Objective: We tested the hypothesis that the matricellular protein thrombospondin-1 (TSP1), through binding to and activation of the cell receptor CD47, inhibits basal and thermal-mediated cutaneous blood flow.

Background: Abnormal and decreased cutaneous blood flow in response to temperature changes or vasoactive agents is a feature of cardiovascular disease and aging. The reasons for decreased cutaneous blood flow remain incompletely understood. Furthermore, a role for matricellular proteins in the regulation skin blood flow has never been proposed.

Methods: C57BL/6 wild type, TSP1-null, and CD47-null 12- and 72-week-old male mice underwent analysis of skin blood flow (SkBF) via laser Doppler in response to thermal stress and vasoactive challenge.

Results: Young and aged TSP1- and CD47-null mice displayed enhanced basal and thermal sensitive SkBF changes compared with age-matched wild type controls. Nitric oxide–mediated increases in SkBF were also greater in null mice. TSP1 and CD47 were expressed in skin from young wild type mice, and both were significantly upregulated in aged animals. Tissue 3’,5’-cyclic guanosine monophosphate, a potent vasodilator, was greater in skin samples from null mice compared with wild type regardless of age. Finally, treating wild type animals with a CD47 monoclonal antibody that inhibits TSP1 activation of CD47 enhanced SkBF in both young and aged animals.

Conclusions: These results suggest that secreted TSP1, via its cognate receptor CD47, acutely modulates SkBF. These data further support therapeutically targeting CD47 to mitigate age-associated loss of SkBF and maximize wound healing.

Decreased skin blood flow in response to temperature changes or vasoactive agents is a feature of cardiovascular disease and aging. The reasons for decreased skin blood flow remain incompletely understood. We show that activated CD47 limits basal, vasoactive, and thermally challenged skin blood flow. Age-associated induction of CD47 further suppresses skin blood flow. Antibody blockade of CD47 increases skin blood flow in young and aged animals.

*Division of Pulmonary, Allergy and Critical Care Medicine

Vascular Medicine Institute

Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA

§Laboratory of Pathology, CCR, NCI, Bethesda, MD.

Reprints: Jeffrey S. Isenberg, MD, MPH, E1258, BST, 200 Lothrop Street, Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261. E-mail: jsi5@pitt.edu.

Disclosure: Funding for this work was provided to J.S.I. by 1RO1HL108954-01 (NIH/NHLBI), 1P01HL103455-01 (NIH), 11BGIA7210001 (AHA), the Vascular Medicine Institute of the University of Pittsburgh, the Institute for Transfusion Medicine, and the Western Pennsylvania Hemophilia Center; to D.D.R. by the Intramural Research Program of the NCI/NIH; and to N.A.R. by APP1016276 C.J. Martin Award (Australian NHMRC). J.S.I. is Chair of the Scientific Advisory Boards of Vasculox, Inc. (St. Louis, MO) and Radiation Control Technologies, Inc. (Gaithersburg, MD).

© 2013 by Lippincott Williams & Wilkins.