A reduction in the vascular smooth muscle cell focal adhesion component syndecan‐4 is associated with abdominal aortic aneurysm formation

Abstract

Background Abdominal aortic aneurysm (AAA) is a serious vascular disease for which there is no effective drug treatment. The incidence of AAA increases significantly as a subject ages, and the molecular mechanism of AAA formation remains elusive. In the present study, we investigated the role of syndecan‐4 (SDC4), an important component of focal adhesions, in AAA formation and its association with phenotypic changes in vascular smooth muscle cells (VSMCs). Methods and results The protein expression levels of SDC4 were significantly decreased in human AAA tissue and those of an AAA mouse model. Moreover, SDC4 knockout (KO) in mice accelerated the formation and rupture of AAAs induced by angiotensin II (Ang II) and calcium chloride (CaCl 2 ) Mechanistically, the decrease in SDC4 led to the transformation of cultured VSMCs from a contractile to a secretory phenotype. The RhoA‐F/G‐actin‐myocardin‐related transcription factor‐A (MRTF‐A) signalling pathway was shown to be involved in SDC4‐dependent VSMC alteration. Sphingosine‐1‐phosphate (S1P), a G‐protein‐coupled receptor, attenuated the AAA formation in SDC4‐KO and wild‐type (WT) mice in response to Ang II and CaCl 2 stimulation. Conclusion We herein demonstrated that silencing SDC4 was associated with increased AAA formation and phenotypic changes in VSMCs via the RhoA‐F/G‐actin‐MRTF‐A pathway. These findings indicated that a reduction in SDC4 expression was an important pathological alteration and potential therapeutic target for AAA formation.

Elucidating VSMC phenotypic transition mechanisms to bridge insights into cardiovascular disease implications

“…AAs, particularly abdominal aortic aneurysms (AAA), are primarily characterized by localized or widespread expansions of the arterial wall, stemming from arterial damage or disease, leading to a compromised vascular integrity. The development of AAs is primarily attributed to the breakdown of extracellular matrix elements and arterial medial layer components like elastin, culminating in diminished vascular wall tension and compromised vascular integrity ( 98 ).…”

The causal relationship between smoking and thoracic aortic aneurysm: Evidence from Mendelian randomization analysis

“…Aortic aneurysms are defined as significant dilations of the aorta exceeding normal diameter by 50% or surpassing 3 cm. [1] A rupture of an aneurysm can precipitate severe internal hemorrhaging, often resulting in fatality; indeed, mortality rates posthospitalization reach 80%, and postoperative death occurs in 50% of surgical interventions for aortic aneurysm rupture. [2,3] In 2017, aortic aneurysms accounted for 167,200 fatalities and the loss of 3 million disability-adjusted life years, as reported by the Global Burden of Disease Study.…”