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Macrophage CD31 Signaling in Dissecting Aortic Aneurysm
Study Questions:
What is the therapeutic potential of a drug-suitable agonist peptide in experimental aortic dissection and intramural hematoma?
Methods:
P8RI, a retro-inverso sequence of the best candidate identified by functional in vitro screening of a peptide library, passed an absorption, distribution, metabolism, excretion, and toxicology analysis. Apo E−/− mice (male, 28-week-old) implanted with angiotensin II-releasing pumps received P8RI (2.5 mg/kg/day) or vehicle from day 14 (n = 10 per group). Leukocytes were analyzed by flow cytometry. Healing features of human and mouse dissected aortic segments were assessed by histology and immunofluorescence. The effect of CD31 on macrophages was evaluated in vitro using cells from CD31−/− mice and P8RI.
Results:
Human and experimental aortic dissection and intramural hematoma were characterized by the infiltration of proinflammatory macrophages. The absence of CD31 enhanced the proinflammatory polarization of macrophages, whereas the CD31 agonist P8RI favored reparative macrophages both in vitro and in vivo. The administration of P8RI after the occurrence of aortic dissection and intramural hematoma prevented aneurysmal transformation by promoting the resolution of intramural hematoma and the production of collagen in dissected aortas in vivo, associated with enrichment of M2 macrophages at the site of injury.
Conclusions:
CD31 signaling promotes the switching of proinflammatory macrophages to the reparative phenotype, and favors the healing of experimental dissected aortas. Treatment with a drug-suitable CD31 agonist may facilitate the clinical management of aortic dissection and intramural hematoma.
Perspective:
Appropriate arterial healing is crucial for the homeostasis of the circulatory system. The outcome of tissue healing after an acute injury depends on resolution of the initial inflammatory phase, and macrophages play a crucial role in this process. Immediately after entering the wound site, circulating monocytes contribute to the demolition phase of wound healing; but for appropriate tissue healing, the monocytes must transition to a reparative phenotype. Wound healing may be delayed or unachieved in the case of dissected aortas, in which blood-derived elements prevent macrophages from switching from the proinflammatory to the reparative phase.
Previously, work found that the administration of a CD31 agonist peptide could reduce the occurrence of dissection and intramural hematoma in a mouse model. In the present study, the CD31 agonist was optimized for further clinical development and used as a curative treatment starting after the occurrence of the aortic complication. It is possible that, with additional refinement and additional study, this could eventually lead to a clinically useful treatment among patients with acute aortic pathology.
Keywords: Aneurysm, Dissecting, Angiotensin II, Aortic Aneurysm, Apolipoproteins E, Hematoma, Homeostasis, Macrophages, Monocytes, Peptide Library, Phenotype, Secondary Prevention, Elective Surgical Procedures, Vascular Diseases
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