Dysregulated Platelet GPIbα–VWF Signalling in Abdominal Aortic Aneurysm formation and Progression
Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
Background
Platelets are critical drivers of thrombo-inflammatory responses in different cardiovascular diseases. Abdominal aortic aneurysm (AAA) is a progressive, life-threatening vascular disorder mainly characterised by chronic inflammation, extracellular matrix degradation, and the formation of a platelet-rich intraluminal thrombus (ILT). Experimental and clinical evidence identified platelets as main players in AAA pathology as evidenced by elevated platelet activation and procoagulant activity that critically contribute to AAA progression.
Methods
The present study investigated the contribution of glycoprotein (GP)Ibα, the von Willebrand factor (VWF)-binding subunit of the platelet GPIb–IX–V complex, to AAA initiation and progression in experimental AAA using the ePPE mouse model and in patients.
Results
Genetic ablation of platelet GPIbα significantly attenuated early aneurysm expansion in experimental AAA, indicating a critical role for GPIbα during the initial stages of aneurysm development. This initial effect was compensated at later time points showing no differences in aneurysm progression between groups. Notably, genetic deletion of GPIbα induced a constitutively hyperactive platelet phenotype already in naive mice that was further amplified during experimental AAA. This elevated platelet hyperactivity was mainly due to increased GPVI activation of platelets 28 days post-surgery. To assess the clinical relevance, spatial profiles of human ILT specimens from patients with AAA were analysed. In the ILT, we detected a highly compartmentalised distribution of GPIbα and VWF with pronounced enrichment within the luminal layer. In parallel, circulating VWF activity as well as platelet surface expression of GPIbα were significantly increased in patients with AAA.
Conclusion
Collectively, these findings identify a dysregulated GPIbα–VWF axis in human AAA pathology, mainly characterised by enhanced platelet GPIbα surface expression and increased activity of circulating VWF.
