Abstract 16017: A Low Burden Mouse Auricle Model for Venous Research
Venous diseases such as deep vein thrombosis or chronic venous insufficiency constitute a substantial cause of morbidity in the western world. Although most of these diseases originate from varicose vein formation, animal models mimicking their development are scarce. Venous valve failure, pregnancy or obesity pose as main risk factors for varicose vein development due to impaired venous return and therefore increased venous filling pressure. Hence, we hypothesized that experimental venous hypertension is sufficient to elicit corresponding detrimental remodeling processes. To this end, we invented a model to evoke venous hypertension by occluding one large vein in the mouse auricle resulting in enhanced tortuosity and growth (~2.5-fold, p<0.001, n=10) of the connected veins and venules within four days. While varicose remodeling was already visible after two days, (tortuous enlargement ~1.6-fold, p<0.05, n=10), high resolution laser doppler perfusion analyses did not exhibit a significant increase in perfusion in corresponding vein segments. Moreover, the easily accessible, nearly two-dimensionally organized venous network allowed detailed immunofluorescence-based investigations of remodeling vein segments. This revealed an increase in MMP-2 abundance and proliferation of vascular cells (~18-fold, p<0.001, n=5) and a decrease in the smooth muscle cell (SMC) differentiation marker myocardin (~2.4-fold, p<0.001, n=6). Additionally, the morphological features of the auricle allowed for transdermal application of water- and DMSO-soluble drugs which have previously been proven to inhibit activation of venous SMCs in vitro. Thus, blockade of activator protein -1 (AP-1) transcriptional activity by specific decoy oligodeoxynucleotides or inhibition of the proteasome by bortezomib (Velcade®) abolished the aforementioned venous remodeling processes without provoking side effects. Based on this model, we demonstrated that therapeutic transdermal inhibition of the transcriptional activity of AP-1 or the proteasome block detrimental venous remodeling evoked by a chronic increase in filling pressure. As drugs are applied locally, the burden for the animal is substantially lower as compared to systemic drug administration.
Author Disclosures: C. Arnold: None. L. Pfisterer: None. M. Hecker: None. T. Korff: None.
- © 2016 by American Heart Association, Inc.