Stone, B, The Role of Glycoprotein VI in Aneurysm Progression

The Role of Glycoprotein VI in Aneurysm Progression

Bailey Stone1, Anthony Spuzillo1, Tyler W. Benson1, Seth Brunner1, Taylor Coughlin1, Caris Wadding-Lee1, Scott J. Cameron2, and A. Phillip Owens III1

1Heart, Lung and Vascular Institute; Division of Cardiovascular Health and Disease; Department of Internal Medicine; The University of Cincinnati; Cincinnati, OH.

2Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Heart Vascular and Thoracic Institute, Department of Cardiovascular Medicine, Section of Vascular Medicine, Cleveland Clinic Foundation, Cleveland, Ohio, USA.

Introduction: Abdominal aortic aneurysms (AAA) are the 13th leading cause of death (estimated from 15 000 to 30 000 people, both primary and contributing) and affect 5% to 10% of the male and 1% of the female population over the age of 65 in the United States. Rupture of AAA frequently causes death. Currently, the only treatment for AAA is surgical intervention and risk factor management. The pathophysiology of AAA is complex and encompasses proteolysis of the extracellular matrix (ECM), degeneration and loss of vascular smooth muscle cells (VSMCs), alteration of endothelial cells, and formation of intraluminal thrombus (ILT), along with an infiltration and activation of immune cells, and penultimate rupture of the aorta. While platelets are critical in both maintaining hemostasis and propagating thrombosis, the role of platelet activation in the development and progression of abdominal aortic aneurysm (AAA) is still poorly understood. The purpose of this study was to investigate how collagen-mediated glycoprotein VI (GPVI) activation of platelets in AAA affects the pathophysiology of this disease.

Methods: To investigate the role of GPVI in AAA development, next generation RNA sequencing was performed on age-matched control aortic tissue, AAA aortic tissue, and AAA intraluminal thrombus (ILT). To determine whether GPVI had effects upon disease progression, mice underwent either the angiotensin II (AngII) model of AAA formation, or the topical elastase model of infrarenal aneurysm formation.  Aneurysms were elicited and mice were monitored with weekly ultrasounds. After two weeks, mice were randomized to a control (IgG–50µg) or treatment (JAQ1–50µg, monoclonal GPVI antibody) cohort via one intraperitoneal injection.

Results: Platelet transcripts comprised 25% of significantly enriched genes in the comparison of AAA thrombus to AAA tissue and control aortic wall, with GPVI increased by 9.1 Log2-FC (P = 3.21E-08).  Circulating GPVI was significantly elevated in platelets isolated from AAA patients versus age-matched controls. Soluble GPVI (sGPVI–indicator of platelet activation), was significantly increased in the plasma of patients with fast-growing AAAs compared to slow-growing AAAs and healthy control subjects.  JAQ1 treatment attenuated aneurysm growth, attenuated macrophage accumulation, and increased survival in both models versus IgG controls. 

Conclusion: Platelets play a critical role in aneurysm pathophysiology resulting in disease progression. Dampening the platelet response in AAA by targeting the GPVI-mediated pathway of activation could be a potential therapeutic for a disease that currently has no pharmacological treatment.

Contact: stoneby@mail.uc.edu

Key Words: vascular, AAA, aneurysm, platelets, blood