Claire Collins

Introduction: Aortic dissections and intramural hematomas (ADIM) result from tears and subsequent rupture of the walls of the aortic tunica intima and vasa vasorum, respectively.^1,2 The absence of therapeutic options to rapidly induce pro-reparative effects exacerbates the size of the injury among other complications, contributing to the need for additional intervention in 25-35% of ADIM patients.² Macrophages are significant contributors to the healing and repair of ADIM; the M1 macrophage phenotype is associated with proinflammatory functions while the M2 phenotype contributes to wound healing.³ Since macrophages can influence the progression of a disease in a pro-inflammatory or pro-reparative manner, regulating their polarization could impact ADIM recovery.⁴ Methods: Bone marrow-derived macrophages (BMDM) were created from CD31+/+ and CD31-/- mice, and the effects of both CD31, a platelet endothelial cell adhesion molecule, and P8RI, a CD31 peptide analog, on macrophage differentiation were tested in vitro by quantifying the presence of M1 and M2 markers for differentiation.² In vivo testing involved administrating 5mg/kg/day of CD31 analog P8RI to 28-week old Apo E-/- mice and following changes in abdominal aorta diameter with weekly ultrasound and collagen content with sirius red staining.² Statistical analysis on the differences between groups was performed using Mann-Whitney U test and analysis of variance, with a p value of <0.05 indicating statistical significance.²  Results: The absence of CD31 signaling in BMDM promoted the presence of the M1 phenotype while CD31 expression resulted in greater presence of the M2 phenotype.² P8RI also significantly increased Arginase I expression (M2 marker) and decreased iNOS and Arginase II expression (M1 markers) on BMDM in vitro.² Aortic ultrasound showed the progression of the aortic dissection stopped in the P8RI treatment group but continued to enlarge in the control.² The P8RI group also demonstrated an increased area of collagen content, indicating greater wound healing as a result of treatment.² Conclusions: This data suggests CD31 agonist drugs like P8RI promote the induction of pro-reparative macrophages, which could reduce the severity of complications in patients with ADIM.^3,4 The CD31 analog method of administration is limited to IV or subcutaneous injection, however, which is only conducive for short-term use.² Implementation of a liposomal system to deliver a CD31 analog may provide a more effective and suitable treatment option and should be further explored.⁵

1. King RW, Bonaca Acute aortic syndromes: a review of what we know and future considerations. Eur Heart J Acute Cardiovasc Care. 2021;10(10):1197-1203. doi:10.1093/ehjacc/zuab106
2. Andreata F, Syvannarath V, Clement M, et al. Macrophage CD31 Signaling in Dissecting Aortic J Am Coll Cardiol. 2018;72(1):45-57. doi:10.1016/j.jacc.2018.04.047
3. Cheng Z, Zhou YZ, Wu Y, et al. Diverse roles of macrophage polarization in aortic aneurysm: destruction and J Transl Med. 2018;16(1):354. Published 2018 Dec 13. doi:10.1186/s12967-018-1731-0
4. Batra R, Suh MK, Carson JS, et al. IL-1β (Interleukin-1β) and TNF-α (Tumor Necrosis Factor-α) Impact Abdominal Aortic Aneurysm Formation by Differential Effects on Macrophage Polarization. Arterioscler Thromb Vasc Biol. 2018;38(2):457-463. doi:10.1161/ATVBAHA.117.310333
5. Zhang G, Xue H, Sun D, Yang S, Tu M, Zeng R. Soft apoptotic-cell-inspired nanoparticles persistently bind to macrophage membranes and promote anti-inflammatory and pro-healing effects. Acta Biomater. 2021;131:452-463. doi:10.1016/j.actbio.2021.07.002