Protease-activated receptors are potential regulators in the development of arterial endofibrosis in high-performance athletes

• Published in: Journal of vascular surgery Vol. 69; no. 4; pp. 1243 - 1250
• Main Authors: Posthuma, Jelle J., Posma, Jens J.N., Schep, Goof, Bender, Mart M.H., van Oerle, Rene, van der Wal, Allard C., ten Cate, Hugo, Spronk, Henri M.H.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-04-2019
• Subjects: Coagulation factors; Endofibrosis; Protease-activated receptors; Vascula fibrosis; Coagulation factors; Vascula fibrosis; Endofibrosis; Protease-activated receptors
• ISSN: 0741-5214; 1097-6809
• DOI: 10.1016/j.jvs.2018.05.220

High-performance athletes can develop symptomatic arterial flow restriction during exercise caused by endofibrosis. The pathogenesis is poorly understood; however, coagulation enzymes, such as tissue factor (TF) and coagulation factor Xa, might contribute to the fibrotic process, which is mainly regulated through activation of protease-activated receptors (PARs). Therefore, the aim of this explorative study was to evaluate the presence of coagulation factors and PARs in endofibrotic tissue, which might be indicative of their potential role in the natural development of endofibrosis.
External iliac arterial specimens with endofibrosis (n = 19) were collected during surgical interventions. As control, arterial segments of the external iliac artery (n = 20) were collected post mortem from individuals with no medical history of cardiovascular disease who donated their body to medical science. Arteries were paraffinized and cut in tissue sections for immunohistochemical analysis. Positive staining within lesions was determined with ImageJ software (National Institutes of Health, Bethesda, Md).
Endofibrotic segments contained a neointima, causing intraluminal stenosis, which was highly positive for collagen (+150%; P < .01) and elastin (+148%; P < .01) in comparison with controls. Intriguingly, endofibrosis was not limited to the intima because collagen (+213%) and elastin (+215%) were also significantly elevated in the media layer of endofibrotic segments. These findings were accompanied by significantly increased α-smooth muscle actin-positive cells, morphologically compatible with the presence of myofibroblasts. In addition, PAR1 and PAR4 and the membrane receptor TF were increased as well as coagulation factor X.
We showed that myofibroblasts and the accompanying collagen and elastin synthesis might be key factors in the development of endofibrosis. The special association with increased presence of PARs, factor X, and TF suggests that protease-mediated cell signaling could be a contributing component in the mechanisms leading to endofibrosis.
We show that endofibrosis is characterized by fibrosis at the luminal side as well as in the media layer of arteries. Remarkably, the amount of medial fibrosis was irrespective of intraluminal stenosis, thereby shedding new light on endofibrosis-related symptoms. Intermittent claudication due to endofibrosis has always been assumed to be a result of intraluminal stenosis. However, our data suggest that a reduced vascular function (eg, arterial stiffness) might explain why some patients develop clinical symptoms suggestive of endofibrosis, with no signs of intraluminal disease on computed tomography angiography or magnetic resonance angiography imaging. These findings have clinical relevance because measuring vascular function might be useful in the diagnostic approach. In addition, this new understanding of the natural development contributes to new targets for treatment.