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

Abstract

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 Data 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. Further, a role for matricellular proteins in the regulation skin blood flow has never been proposed. Methods C57BL/6 wild type, TSP1- 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 SkFB changes compared to 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 (cGMP), a potent vasodilator, was greater in skin samples from null mice compared to 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 The above 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.

Regulation of Cellular Redox Signaling by Matricellular Proteins in Vascular Biology, Immunology, and Cancer

“…Mechanistic studies demonstrated that TSP1 blocked the dephosphorylation of myosin light chain-2 induced by treating these cells with NO and thereby promoted F-actin assembly and contraction of the smooth muscle cells. Notably, the elevated tissue cGMP levels found in young male Thbs1 -/-mice persisted as those mice were aged to 12-16 months, but cGMP levels fell significantly with age in male WT mice (86), consistent with the reported elevations in tissue TSP1 and CD47 levels with aging (19,105,207,213). Thus, TSP1 physiologically opposes the activity of NO to regulate vascular tone, but this balance becomes perturbed with increasing age.…”

“…The ability of a CD47 antibody and antisense morpholino suppression of CD47 to restore normal ischemic injury responses to aged WT mice is proof of principle that therapeutics targeting this pathway could have broad clinical applications (86,213).…”

“…That aging alone may induce matricellular expression in people was recently suggested by findings of upregulation of platelet TSP1 in otherwise healthy adults compared with healthy children (33). TSP1 and CD47 expression in the skin of WT mice increased with age and was associated with a loss in tissue blood flow (213), whereas skeletal muscle blood flow in response to ischemia or vasodilators was not diminished in aged Thbs1…”

CD47 regulates renal tubular epithelial cell self-renewal and proliferation following renal ischemia reperfusion

“…To validate our model of renal IRI, we exposed wild-type (WT) mice to titrated degrees of bilateral renal ischemia (10,15, and 20 minutes), as we have reported, 18,26 and assessed renal injury at 1, 3, or 7 days after reperfusion. Ten minutes of warm ischemia had minimal effect on renal function, whereas serum creatinine was moderately increased after 15 minutes of ischemia at 24-hour reperfusion but returned toward baseline by 7 days (Figure 1a).…”

Invoking the power of thrombospondins: Regulation of thrombospondins expression

“…Levels of TSPs increase in multiple tissues with age (21, 116, 179-182). The significance of this increase in TSPs production is still unclear, although in some tissues it appears to be beneficial (21, 26, 179, 180).…”