CD47 Promotes Age-Associated Deterioration in Angiogenesis, Blood Flow and Glucose Homeostasis

Abstract

The aged population is currently at its highest level in human history and is expected to increase further in the coming years. In humans, aging is accompanied by impaired angiogenesis, diminished blood flow and altered metabolism, among others. A cellular mechanism that impinges upon these manifestations of aging can be a suitable target for therapeutic intervention. Here we identify cell surface receptor CD47 as a novel age-sensitive driver of vascular and metabolic dysfunction. With the natural aging process, CD47 and its ligand thrombospondin-1 were increased, concurrent with a reduction of self-renewal transcription factors OCT4, SOX2, KLF4 and cMYC (OSKM) in arteries from aged wild-type mice and older human subjects compared to younger controls. These perturbations were prevented in arteries from aged CD47-null mice. Arterial endothelial cells isolated from aged wild-type mice displayed cellular exhaustion with decreased proliferation, migration and tube formation compared to cells from aged CD47-null mice. CD47 suppressed ex vivo sprouting, in vivo angiogenesis and skeletal muscle blood flow in aged wild-type mice. Treatment of arteries from older humans with a CD47 blocking antibody mitigated the age-related deterioration in angiogenesis. Finally, aged CD47-null mice were resistant to age- and diet-associated weight gain, glucose intolerance and insulin desensitization. These results indicate that the CD47-mediated signaling maladapts during aging to broadly impair endothelial self-renewal, angiogenesis, perfusion and glucose homeostasis. Our findings provide a strong rationale for therapeutically targeting CD47 to minimize these dysfunctions during aging.

Thrombospondin-1 CD47 Signalling: From Mechanisms to Medicine

“…They display comparable structural features that consist of well-defined binding domains that link to proteoglycans and integrins [ 4 , 5 ]. Thrombospondins have diverse physiological and pathophysiological tissue-specific actions that include effects on vascular responsiveness [ 6 , 7 ] and angiogenesis [ 8 , 9 , 10 ], platelet activation [ 11 , 12 ], inflammation [ 13 , 14 ], and cell death [ 15 ] that directly impact on wound healing and tumorigenesis.…”

“…When CD47 expression was absent in human and murine endothelial cells, VEGFR2 phosphorylation was no longer inhibited and angiogenic responses improved [ 10 ]. A recent study revealed that the anti-angiogenic effects of CD47 escalate with age in humans and mice, defining this pathway as a potential therapeutic target in age-associated vascular impairments [ 8 ].…”

“…Thus, TSP1-CD47 signalling in cells not only supresses angiogenesis but also potentiates vascular pathology by inhibiting the cell cycle and inducing a senescent cellular phenotype [ 80 ]. The ageing process alone increases TSP1 and CD47 levels in the vasculature of both humans and mice, leading to age-associated impairment of vital cellular processes, including blood flow, angiogenesis, cellular self-renewal, and glucose homeostasis [ 8 ]. These manifestations were significantly improved in CD47-deficient mice suggesting that pharmacologic inhibition of CD47 could be useful in treating ageing-associated disorders.…”

Thrombospondin 1 in Metabolic Diseases

“…TSP1 and CD47 are upregulated in aged arteries ( 45 ), and when aortic rings from older individuals were treated with an antibody against CD47, they showed similar sprouting to the aortic rings treated with vascular endothelial growth factor (VEGF). These results revel new and exciting insights into reversing atherosclerosis and the aging process ( 45 ).…”

“…As age predisposes the body to insulin resistance and hyperglycemia, CD47 will further inhibit SMCs proliferation and angiogenesis. Indeed, CD47-null aging mice have demonstrated better responses to glucose than control mice ( 45 ).…”