Annexin A1: A Promising Target for Preventing Aortic Dissections

Aortic dissection (AD) is a serious vascular disease characterized by a tearing of the aortic wall. Smooth muscle cells (SMCs) play a pivotal role in maintaining the integrity of the aortic wall, and SMC phenotypic switching has been identified as a key mechanism of AD formation.^{1, 2} In a recent issue of Cardiovascular Research,³ Zhou et al. reported the contribution of annexin A1 (ANXA1) to AD development associated with phenotypic switching of aortic SMCs (Figure).

ANXA1 is a member of the annexin superfamily of Ca²⁺ dependent phospholipid-binding proteins and is present in multiple cell types, including leukocytes and vascular SMCs.^{4, 5} ANXA1 was found initially as a second messenger of glucocorticoids that inhibits phospholipase A2 and prostaglandin biosynthesis.⁶ A number of studies have shown its anti-inflammatory function. Subsequently, protective effects of ANXA1 were reported in several cardiovascular diseases, such as myocardial infarction and atherosclerosis.⁴ In the study of Zhao et al,³ the authors investigated the role of ANXA1 in the pathophysiology of ADs (Figure). First, the authors characterized the abundance and distribution of ANXA1 in mouse ADs induced by co-administration of β-aminopropionitrile (BAPN) and angiotensin II (AngII). In BAPN/AngII-induced ADs, ANXA1 has increased abundance in aortic SMCs compared to control aortas. Then, ANXA1 was manipulated to investigate its function in AD development. Global deletion of ANXA1 augmented ADs in mice co-administered with BAPN and AngII. SMC-specific ANXA1 deletion also enhanced BAPN and AngII-induced AD formation. Of potential therapeutic relevance, the effect of Ac2-26, a mimetic peptide of ANXA1, was examined in development of ADs. Of note, ADs induced by BAPN and AngII co-administration were attenuated by Ac2-26. These data indicate that ANXA1 in SMCs protects against AD formation. Since ANXA1 was highly abundant in SMCs of dissected aortas, the authors focused on SMC functions, in particular its phenotypic switching, to elucidate ANXA1-mediated mechanisms of AD formation. Compared to normal aortas, ANXA1 deletion had a lower abundance of contractile proteins, such as MYH11, ACTA2, CNN1, and TAGLN. In contrast, several proteinases and inflammatory cytokines, such as MMP2, MMP9, TNFα, CCL2, and IL6, were increased by whole-body ANXA1 deletion. The authors also found decreased MYL9 and JunB that regulated vascular SMC contractility.⁷ For translational purposes, the increase of ANXA1 and the presence of SMC phenotypic switching were also determined in human AD samples.

Under physiological conditions, most aortic SMCs display a contractile phenotype.⁸ During AD progression, SMCs are switched into a synthetic phenotype that is characterized by decreased contractile proteins.⁸ Synthetic SMCs secrete proteolytic enzymes. Proteolytic enzymes degrade extracellular matrix and facilitate detachment of SMCs from elastic fibers, which disrupt the integrity of the aortic wall. Zhou et al. demonstrated that ANXA1 deletion augmented AD formation accompanied by a decrease of contractile molecules.³ Thus, ANXA1 is required for maintenance of aortic integrity and SMC homeostasis. It is important to note that synthetic SMCs also secrete inflammatory cytokines. ANXA1 has been identified as a potent anti-inflammatory molecule,⁹ and inflammatory responses are involved in the pathophysiology of ADs.¹⁰ Thus, the anti-inflammatory functions of ANXA1 may also contribute to ANXA1-mediated mechanisms of AD formation.

Despite compelling evidence that SMCs exert a pivotal role in AD formation, this study raises a question of why ADs occur in a region-specific manner, predominantly in the ascending aorta and the proximal descending thoracic aorta. SMCs are distributed across the aorta from the aortic root to the distal abdominal aorta; however, the proximal thoracic aorta is susceptible to AD formation compared to other aortic regions. One mechanism of the regional specificity of ADs is the contribution of embryonic origins of SMCs. Embryonic origins of SMCs in the thoracic aortas are heterogeneous and exhibit a distinct distribution.^{11, 12} SMCs from different embryonic origins have distinct functions in maintaining aortic wall integrity.^{12, 13} It would be interesting to investigate the embryonic origin-specific role of ANXA1 and SMC phenotypic switching in AD formation.

The determination of molecular mechanisms is often challenging in AD research. Comparing between normal and diseased tissues is a common mode for elucidating disease process. However, it is not feasible to discern whether differences in the tissues of these groups are a cause or a consequence of the disease progression using this approach. In addition, since ADs are initiated by disruption of the intima, aortic pathologies, such as medial dissection and intramural hematoma, may be consequences of the intimal disruption. A number of studies have uncovered mechanisms of ADs, but the initial process and mechanism remain obscure. Thus, there is a vital need to investigate the molecular basis of ADs just before pathological process starts. However, it is technically difficult to anticipate the initiation of ADs. Further insight may be garnered by detailed and sequential characterization of AD histology targeted at the entry site of ADs as well as its adjacent area. This approach could provide insights into understanding the complex mechanism of ADs.

The study by Zhou et al.³ demonstrates a critical role of ANXA1 in the pathophysiology of ADs and SMC functions. We look forward to future study to explore the role of ANXA1 on the initial process of AD formation in addition to disease progression.