Wednesday, April 2, 2025
4/2/2025
Novel Mechanisms underlying abdominal aortic aneurysm progression - Summary/Abstract Abdominal aortic aneurysm (AAA) is a potentially lethal disease that lacks pharmacological treatment. Although vascular inflammation is the initial event leading to AAA formation, aorta rupture due to artery wall weakening is responsible for the high mortality rate in this silent killer. Aortic wall weakening in AAA is primarily caused by aorta media degeneration, elastin breakage and impaired adventitia response. The media degeneration is driven by programmed cell death (e.g., apoptosis and necroptosis) of medial smooth muscle cells (SMC). However, there are critical knowledge gaps concerning mechanism(s) or key factor(s) governing SMC survival in aortic wall. Moreover, adventitia thickening due to fibroblastic response is crucial for strengthening aorta wall and impeding AAA progression. Compromised adventitial responses along with medial degeneration make the aorta highly vulnerable to rupture. However, it remains largely unknown how the adventitia fibroblastic response is regulated. Exciting preliminary data indicate that Smad2 is downregulated in both mouse and human AAA lesions. Smad2 deficiency with SM22α-Cre mice (S2sm22-/-) exacerbates AAA formation/dissection in both angiotensin II (Ang II) infusion and elastase models. S2sm22-/- aggravates elastin fragmentation, causes larger aorta dilation and greater SMC loss with less adventitia thickening than wildtype (WT) ApoE-/- mice in AAA. Importantly, Smad2 deficiency exacerbates SMC necroptosis both in vivo in aorta media and in vitro in culture SMCs. Moreover, lineage tracing studies indicate that Smad2 deficiency in SMCs attenuates SMC trans-differentiation to adventitial Sca1 (advSca1) cells and diminishes adventitial fibroblast proliferation and collagen deposition. These compelling data strongly support a novel hypothesis that SMC- driven Smad2 mitigates AAA progression by alleviating SMC necroptosis in aorta media while promoting protective fibroblast response in adventitia. Using primary mouse and human SMCs, in vivo Smad2 SMC- specific knockout mouse and two AAA models combining with molecular, cellular, histological, and cutting- edge CUT&RUN sequencing and single cell RNA sequencing analyses, the hypothesis will be tested by two specific aims: Aim 1 is to determine the impact of Smad2 deficiency on AAA formation/dissection; and Aim 2 is to establish molecular mechanisms by which Smad2 preserves aortic wall integrity essential for hindering AAA formation/dissection. Successful completion of the proposed studies will establish novel mechanisms regulating SMC necroptosis and adventitial protective responses, which are likely to advance our understanding of the AAA progression and dissection and ultimately lead to novel strategies for developing effective therapeutics to treat AAA/dissection.
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