Clin Res Cardiol (2021). 10.1007/s00392-021-01933-9

F. Brack1, T. Suvorava1, J. W. Fischer1, M. Grandoch1
1Institut für Pharmakologie und Klinische Pharmakologie, Universitätsklinikum Düsseldorf, Düsseldorf;

Abdominal aortic aneurysm (AAA) is defined as a permanent dilation of the infrarenal aortic artery as a consequence of non-modifiable (age, male sex, genetic association) and modifiable risk factors such as smoking and advanced atherosclerosis. This process is accompanied by a continuous degradation of the extracellular matrix (ECM), apoptosis of smooth muscle cells (SMCs) and infiltration of immune cells leading to progressive dilatation of the aortic wall and potential arterial wall rupture. Previous work has shown that hyaluronan (HA), a glycosaminoglycan of the ECM, and specifically HA synthase (HAS)-3 affect the inflammatory response, alter the fibroblast phenotype. Therefore, HA is considered as a promising target in the pathogenesis of AAA. Thus, the aim of the study was to elucidate the role of HA and specifically HAS3 in AAA formation.

Male Apoe-knockout (KO) and Apoe/Has3-double deficient (DKO) mice were subjected to a model of Angiotensin II (AngII)-induced AAA. To get insights into the progression and formation of AAA, detailed longitudinal ultrasound screenings were performed. Aortae were collected for immunohistochemical stainings of elastin and collagen. In addition, flow cytometric analysis of the diseased aorta, circulation and of the bone marrow was performed.

Our preliminary data showed improved survival of Apoe/Has3-DKO mice in the AngII-induced AAA model after 28 days of AngII treatment. Furthermore, we observed an increased area of the aortic media and a trend towards fewer elastic breaks per aortic cross section thereby suggesting a more elastic aortic wall in Apoe/Has3-DKO mice compared to Apoe-knockout mice. In addition, more circulating myeloid leukocytes and total monocytes (Ly6C high combined with Ly6C low monocytes) were identified after 7 days of AngII treatment in Apoe/Has3-DKO mice. In contrast, fewer myeloid leukocytes and macrophages were detected in the aortic wall of Apoe/Has3-DKO mice.

Summarized, targeted deletion of HAS3 resulted in attenuation of AAA development. Mechanistically, reduced immune cell infiltration into the aortic and subsequent fewer elastic breaks may play a pivotal role in the progression of AAA.