Aortic dissection (AD) is a severe and often deadly cardiovascular condition. It occurs when the inner layer of the aorta, the body’s largest artery, tears—allowing blood to surge through and split the artery wall into layers. This can disrupt blood flow to vital organs and lead to sudden death. Without immediate intervention, the mortality rate can increase by 1%–2% every hour during the first 48 hours, reaching as high as 90% within a week.
Currently, surgery is the only life-saving treatment for AD. Despite ongoing research, there are no effective medications to halt or reverse the disease. Understanding what triggers and drives the dissection process at the molecular level remains an urgent scientific challenge.
In a recent study published in Biomolecules and Biomedicine, researchers from Anhui Medical University and The First Affiliated Hospital of Bengbu Medical University explored the role of ERBB4, a receptor protein involved in cell signaling, in the progression of aortic dissection. Their findings suggest that ERBB4 may be a key driver of disease progression and a promising target for future therapies.
Vascular Cells Under Stress
Aortic dissection is not just a mechanical failure of the artery wall. It also involves biological changes at the cellular level, especially in vascular smooth muscle cells (VSMCs). These cells are critical for maintaining the structural integrity and function of blood vessels.
Under disease conditions, VSMCs can switch from a stable, contractile form to a more active, migratory, and proliferative form. This “phenotypic switching” weakens the aortic wall by reducing its contractility and promoting inflammation and remodeling. This cellular behavior is thought to play a central role in the progression of AD.
In this study, the researchers examined thoracic aortic tissue samples from AD patients and controls. Using immunohistochemistry and western blot analysis, they observed a marked reduction in α-actin and TAGLN, two markers of healthy, contractile VSMCs. At the same time, levels of SPP1 and epiregulin—proteins associated with proliferation and inflammation—were significantly increased. This confirmed a shift in VSMC phenotype in AD tissues.
RNA Sequencing Reveals a Suspect
To uncover the molecular players involved in this process, the team conducted RNA sequencing on aortic tissue samples. They identified 1,878 upregulated and 3,440 downregulated genes in AD tissues compared to controls.
Further bioinformatics analysis highlighted several biological processes associated with these genes, including leukocyte migration, integrin binding, focal adhesion, and NF-κB signaling—pathways already known to be involved in inflammation and vascular disease.
Among the genes that stood out were KRT16, VCAN, and ERBB4. Based on expression levels and known roles in vascular biology, the researchers chose to focus on ERBB4 for deeper investigation.
ERBB4 Knockdown Reduces Harmful Cell Activity
ERBB4, also known as HER4, is part of the epidermal growth factor receptor (EGFR) family. These proteins regulate many essential cellular functions such as growth, differentiation, and survival. While ERBB4 has been studied in cancer and nervous system development, its role in aortic dissection was previously unknown.
To test its function, the team used siRNA to silence ERBB4 in human aortic smooth muscle cells (HASMCs) cultured in high-glucose conditions. Among the three siRNA sequences tested, siRNA-2 was the most effective in reducing ERBB4 expression.
Silencing ERBB4 had multiple effects on cell behavior:
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Reduced viability and proliferation, shown by cell viability assays and colony formation tests.
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Slower migration, as measured by wound healing and transwell assays.
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Decreased tube formation, indicating reduced angiogenic activity.
Flow cytometry confirmed that ERBB4 knockdown led to cell cycle arrest at the G1/S and G2/M checkpoints, further limiting the cells’ ability to proliferate.
Animal Study Confirms Protective Effects
To validate these findings in vivo, the researchers used a rat model of aortic dissection, induced with β-aminopropionitrile. Rats were divided into control and ERBB4-knockdown groups, with gene silencing achieved via adenovirus injection.
Histological analysis showed that ERBB4 knockdown reduced inflammatory cell infiltration in the aortic wall. Masson staining revealed improved collagen fiber contractility, while elastic fibers appeared denser and more regularly arranged, although some remained partially damaged.
These changes suggest that targeting ERBB4 can stabilize the aortic wall structure and potentially limit dissection progression.
Mechanism: Inhibiting Inflammatory and Adhesion Pathways
The study also investigated how ERBB4 might influence disease mechanisms. Bioinformatics analysis had pointed to integrin binding and NF-κB signaling as possible pathways. These are involved in cell adhesion, immune response, and inflammation.
Western blot results showed that ERBB4 knockdown suppressed the expression of integrin-related proteins (CD151, ITGAE, and ITGB5) as well as key NF-κB pathway markers (p-IκBα and p-NF-κB-65). These molecular changes likely contribute to the observed reductions in inflammation and cellular activity.
What This Means for Aortic Dissection Treatment
The findings from this study suggest that ERBB4 is not just a bystander but a key player in the pathogenesis of aortic dissection. By promoting VSMC switching, inflammation, and structural degradation, ERBB4 appears to drive disease progression.
Targeting ERBB4 could offer a novel therapeutic approach—possibly through gene therapy or small-molecule inhibitors—to reduce inflammation, improve vascular structure, and slow or prevent dissection development.
Limitations and Next Steps
While the results are promising, the authors caution that more work is needed:
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The long-term effects of ERBB4 suppression remain unknown.
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Rodent models do not fully capture the complexity of human AD.
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The safety and delivery mechanisms of ERBB4-targeting therapies require further study.
Despite these challenges, the study provides a strong foundation for future preclinical and clinical research into ERBB4 as a therapeutic target.
Conclusion
This research offers new insight into the molecular basis of aortic dissection and identifies ERBB4 as a potential target for therapy. By interfering with ERBB4 signaling, it may be possible to slow disease progression, protect the aortic wall, and ultimately offer new treatment strategies for patients facing this life-threatening condition.
The translation of the preceding English text in Chinese:
主动脉夹层（AD）是一种严重且常致命的心血管疾病。
当主动脉（人体最大的动脉）内层撕裂时，血液会迅速进入撕裂处并将动脉壁劈开形成多个层次。这种情况可能中断对重要器官的供血，甚至导致猝死。如果不立即干预，死亡率在最初48小时内每小时可增加1%–2%，一周内高达90%。
目前，手术是治疗AD的唯一有效手段。尽管相关研究不断推进，但尚无药物可以有效阻止或逆转该疾病。在分子层面上理解夹层发生的触发因素和驱动机制，仍是一个亟需解决的科学难题。
在最近发表于《Biomolecules and Biomedicine》的一项研究中，来自安徽医科大学和蚌埠医学院第一附属医院的研究人员探讨了细胞信号受体蛋白ERBB4在主动脉夹层进展中的作用。研究结果表明，ERBB4可能是推动疾病发展的关键因子，也可能成为未来治疗的靶点。
血管细胞承受压力
主动脉夹层不仅仅是动脉壁的机械性破裂，还涉及血管平滑肌细胞（VSMCs）层面的生物学变化。这些细胞对维持血管结构和功能至关重要。
在疾病状态下，VSMCs可由稳定的收缩型向迁移性强、增殖活跃的表型转变。这种“表型转变”会削弱主动脉壁的收缩能力，促进炎症和重构过程，被认为是AD进展的核心机制。
本研究中，研究人员分析了AD患者与对照者的胸主动脉组织样本。通过免疫组化和Western blot分析，他们发现健康VSMC标志物α-肌动蛋白（α-actin）和转录调节蛋白TAGLN显著减少，而与增殖和炎症相关的SPP1和表皮调节蛋白epiregulin显著增加，证实了AD组织中VSMCs的表型发生了变化。
RNA测序揭示关键因子
为探究其中的分子机制，研究团队对主动脉组织样本进行了RNA测序。在AD组织中，相较于对照组，共检测到1,878个上调基因和3,440个下调基因。
生物信息学分析显示，这些基因涉及多个生物过程，包括白细胞迁移、整合素结合、黏附斑形成和NF-κB信号通路，这些都是与炎症和血管病变相关的经典通路。
在这些基因中，KRT16、VCAN 和 ERBB4尤为突出。考虑到其表达水平及其在血管生物学中的潜在作用，研究者决定深入研究ERBB4。
ERBB4下调可减少有害细胞行为
ERBB4，又称HER4，是表皮生长因子受体（EGFR）家族成员，调控细胞生长、分化和生存等多种基本功能。尽管ERBB4已在癌症和神经系统发育中有所研究，其在AD中的作用此前尚不明确。
为了探究其功能，研究人员在高糖培养条件下使用siRNA敲低人主动脉平滑肌细胞（HASMCs）中的ERBB4。在3种siRNA序列中，siRNA-2效果最显著。
ERBB4敲低对细胞行为有多个影响：
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细胞活性和增殖能力下降（通过活性测定和克隆形成实验验证）；
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迁移能力减弱（通过划痕实验和Transwell迁移实验评估）；
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管腔形成能力下降，提示血管生成活性减弱；
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流式细胞术结果显示细胞周期在G1/S和G2/M阶段阻滞，进一步抑制细胞增殖。
动物实验验证保护作用
为在体内验证这一发现，研究人员构建了β-氨基丙腈诱导的大鼠AD模型，并将其分为对照组和ERBB4敲低组，后者通过腺病毒注射实现基因沉默。
组织学分析表明，ERBB4敲低显著减少了主动脉壁的炎性细胞浸润。Masson染色显示胶原纤维收缩性改善，弹性纤维排列更致密且规则，尽管仍有部分受损。
这些改变提示，靶向ERBB4有可能稳定主动脉壁结构，限制夹层进展。
机制：抑制炎症与黏附通路
研究还探讨了ERBB4影响疾病机制的具体方式。生物信息学分析提示整合素结合与NF-κB信号通路是关键相关机制，这些通路在细胞黏附、免疫反应和炎症中发挥作用。
Western blot结果显示，ERBB4敲低抑制了多种整合素相关蛋白（CD151、ITGAE和ITGB5）以及NF-κB通路关键蛋白（p-IκBα和p-NF-κB-65）的表达，这可能解释了炎症和细胞活性下降的现象。
对主动脉夹层治疗的意义
该研究结果表明，ERBB4不仅是一个旁观者，而是AD发病机制中的关键因子。通过促进VSMC表型转变、炎症和结构破坏，ERBB4推动了疾病的发展。
因此，靶向ERBB4（如采用基因治疗或小分子抑制剂）可能成为一种新型治疗策略，有望减轻炎症、改善血管结构，延缓或阻止夹层的形成与发展。
研究局限与后续方向
尽管研究结果令人鼓舞，作者仍指出需进一步研究：
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ERBB4长期抑制的效果尚不明确；
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大鼠模型不能完全模拟人类AD的复杂性；
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靶向ERBB4治疗的安全性与递送机制仍需优化。
尽管存在挑战，这项研究为ERBB4作为治疗靶点的临床前研究奠定了坚实基础。
结论
本研究揭示了主动脉夹层的分子基础，明确了ERBB4作为潜在治疗靶点的重要性。通过干预ERBB4信号通路，有可能延缓疾病进展、保护主动脉结构，为应对这一危及生命的疾病提供全新治疗方向。
Reference:
Yu Shi, Jinjin Meng, Shengqiang Zhang, Shaofeng Yang, Ge Liu, Zhen Wu, Chongwen Shen, Chao Shi
ERBB4 as a therapeutic target in aortic dissection: Implications for cell-based therapies in vascular regeneration.
Biomol Biomed [Internet]. 2025 Mar. 14 [cited 2025 Jun. 5];
Available from: https://www.bjbms.org/ojs/index.php/bjbms/article/view/11925
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