The perspective of cAMP/cGMP signaling and cyclic nucleotide phosphodiesterases in aortic aneurysm and dissection

Abstract

Aortic aneurysm (AA) and dissection (AD) are aortic diseases caused primarily by medial layer degeneration and perivascular inflammation. They are lethal when the rupture happens. Vascular smooth muscle cells (SMCs) play critical roles in the pathogenesis of medial degeneration, characterized by SMC loss and elastin fiber degradation. Many molecular pathways, including cyclic nucleotide signaling, have been reported in regulating vascular SMC functions, matrix remodeling, and vascular structure integrity. Intracellular cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) are second messengers that mediate intracellular signaling transduction through activating effectors, such as protein kinase A (PKA) and PKG, respectively. cAMP and cGMP are synthesized by adenylyl cyclase (AC) and guanylyl cyclase (GC), respectively, and degraded by cyclic nucleotide phosphodiesterases (PDEs). In this review, we will discuss the roles and mechanisms of cAMP/cGMP signaling and PDEs in AA/AD formation and progression and the potential of PDE inhibitors in AA/AD, whether they are beneficial or detrimental. We also performed database analysis and summarized the results showing PDEs with significant expression changes under AA/AD, which should provide rationales for future research on PDEs in AA/AD.

Keywords: Aortic aneurysm; Aortic dissection; GPCR; PDE; cAMP; cGMP.

Figure 1.

The functions of GPCR in aortic aneurysm development. A_2aR alleviates AAA development by suppressing MMP production in vascular SMCs and pro-inflammatory cytokine production in T cells. EP4 promotes AAA development through mediating IL-6 expression in both vascular SMC and macrophages. DP2 promotes AAA development mainly through mediating T-cell activation. A_2bR suppresses proliferation in vascular SMC. β-AR inhibits vascular SMC migration, relaxation, and proliferation. EP2 promotes vascular SMC proliferation and activates NF-kB signaling in endothelial cells and macrophages. However, the roles of A_2bR, β-AR, and EP2 in AAA development remain unknown.

Figure 2.

The role of different PDEs in aortic aneurysm/dissection development. PDE1C contributes to AAA by antagonizing cAMP mediated SIRT1 activation and accelerating vascular SMC senescence. PDE3A contributes to AAA development by promoting elastin degradation, MMP production, and inflammation. PDE4B is mainly expressed in immune cells. PDE4B mediates perivascular inflammation by antagonizing the anti-inflammatory cAMP-signaling in immune cells. PDE4D contributes to AAA by antagonizing the cAMP/PKA/p-BAD signaling pathway and mediating vascular SMC apoptosis. PDE5A inactivation contributes to AAA may be due to promoting the cGMP/PKG/MLCP pathway and vascular SMC relaxation. The vascular contractile function is important for minimizing vessel wall stress. PDE1A is mainly expressed in vascular SMC. PDE7 is mainly expressed in immune cells, such as T cells. The roles of PDE1A and PDE7 in AAA development remains unknown. Bad, BCL2-antagonist of cell death; MLC, myosin light chain.

Figure 3.

Sc-RNA seq reveals different PDE expression in the aorta (re-analyzed from GSE155468). A. PDE expression in the normal aorta of ECs, SMCs, fibroblast FBs, and immune cells. B. PDE1A expression in normal condition (control) and ascending thoracic aortic aneurysm (ATAA). C. PDE7A expression in normal condition (control) and ascending thoracic aortic aneurysm (ATAA). EC, endothelial cell; FB, fibroblast; MSC, mesenchymal stem cell; SMC, smooth muscle cell.