MFAP4 Deficiency Attenuates Angiotensin II-Induced Abdominal Aortic Aneurysm Formation Through Regulation of Macrophage Infiltration and Activity

Abstract

Objective: Abdominal aortic aneurysm (AAA) is a common age-related vascular disease characterized by progressive weakening and dilatation of the aortic wall. Microfibrillar-associated protein 4 (MFAP4) is an extracellular matrix (ECM) protein involved in the induction of vascular remodeling. This study aimed to investigate if MFAP4 facilitates the development of AAA and characterize the underlying MFAP4-mediated mechanisms.Approach and Results: Double apolipoprotein E- and Mfap4-deficient (ApoE−/−Mfap4−/−) and control apolipoprotein E-deficient (ApoE−/−) mice were infused subcutaneously with angiotensin II (Ang II) for 28 days. Mfap4 expression was localized within the adventitial and medial layers and was upregulated after Ang II treatment. While Ang II-induced blood pressure increase was independent of Mfap4 genotype, ApoE−/−Mfap4−/− mice exhibited significantly lower AAA incidence and reduced maximal aortic diameter compared to ApoE−/− littermates. The ApoE−/−Mfap4−/− AAAs were further characterized by reduced macrophage infiltration, matrix metalloproteinase (MMP)-2 and MMP-9 activity, proliferative activity, collagen content, and elastic membrane disruption. MFAP4 deficiency also attenuated activation of integrin- and TGF-β-related signaling within the adventitial layer of AAA tissues. Finally, MFAP4 stimulation promoted human monocyte migration and significantly upregulated MMP-9 activity in macrophage-like THP-1 cells.Conclusion: This study demonstrates that MFAP4 induces macrophage-rich inflammation, MMP activity, and maladaptive remodeling of the ECM within the vessel wall, leading to an acceleration of AAA development and progression. Collectively, our findings suggest that MFAP4 is an essential aggravator of AAA pathology that acts through regulation of monocyte influx and MMP production.

MFAP4-Mediated Effects in Elastic Fiber Homeostasis, Integrin Signaling and Cancer, and Its Role in Teleost Fish

“…In line with that, shRNA-based MFAP4 silencing in TGF-β1-stimulated cardiac fibroblasts resulted in significant downregulation of Col1a1, fibronectin, α-SMA and Col3, and the importance of MFAP4 in activating PI3K, AKT and MEK1/2-ERK1/2 signaling pathways was further validated [79]. In agreement with that, MFAP4 deficiency attenuated aortic collagen deposition as well as FAK and TGF-β pathway activation in an Ang II-induced abdominal aortic aneurysm model resulting in reduced aneurysm size [78].…”

“…MFAP4 was found to promote vascular SMC proliferation and migration through activation of FAK and downstream mediators including PI3K and ERK after carotid artery ligation-mediated injury as well as in human aortic vascular SMCs in vitro [61]. MFAP4 also mediated integrin-dependent direct monocyte recruitment important in pathological remodeling in both neointima formation and aortic aneurysms [78]. Furthermore, the interplay between MFAP4 and integrin signaling has been associated with cardiac remodeling.…”

Single-cell transcriptome in silico analysis reveals conserved regulatory programs in macrophages/monocytes of abdominal aortic aneurysm from multiple mouse models and human

“…Macrophages were mainly derived from circulating monocytes and the main inflammatory cell types in AAA lesions ( 5 ). Monocytes adhesion, migration, and MMP-9 production all increased in AAA patients, leading to aneurysm expansion ( 35 ). Mφ/Mo were extracted for analysis and a total of 7 subtypes were defined, which expressed diverse factors and were highly dynamic and heterogeneous.…”

Identification and validation of key genes associated with atrial fibrillation in the elderly

“…MFAP4 is involved in cardiac remodeling and its deletion attenuates the progression of angiotensin II-induced atrial fibrosis and AF ( 53 ). In addition, MFAP4 is associated with aneurysms and peripheral arterial diseases ( 54 ).…”