Local adventitial anti-angiogenic gene therapy reduces growth of vasa-vasorum and in-stent restenosis in WHHL rabbits

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Hytonen , J P , Taavitsainen , J , Laitinen , J T T , Partanen , A , Alitalo , K , Leppänen , O & Ylä-Herttuala , S 2018 , ' Local adventitial anti-angiogenic gene therapy reduces growth of vasa-vasorum and in-stent restenosis in WHHL rabbits ' , Journal of Molecular and Cellular Cardiology , vol. 121 , pp. 145-154 . https://doi.org/10.1016/j.yjmcc.2018.07.007

Title: Local adventitial anti-angiogenic gene therapy reduces growth of vasa-vasorum and in-stent restenosis in WHHL rabbits
Author: Hytonen, Jarkko P.; Taavitsainen, Jouni; Laitinen, Johannes T. T.; Partanen, Anna; Alitalo, Kari; Leppänen, Olli; Ylä-Herttuala, Seppo
Contributor organization: Translational Cancer Biology (TCB) Research Programme
Kari Alitalo / Principal Investigator
Research Programs Unit
University of Helsinki
Date: 2018-08
Language: eng
Number of pages: 10
Belongs to series: Journal of Molecular and Cellular Cardiology
ISSN: 0022-2828
DOI: https://doi.org/10.1016/j.yjmcc.2018.07.007
URI: http://hdl.handle.net/10138/305124
Abstract: Background: Antiproliferative drugs in drug eluting stents (DES) are associated with complications due to impaired re-endothelialization. Additionally, adventitial neovascularization has been suggested to contribute to in-stent restenosis (ISR). Since Vascular Endothelial Growth Factors (VEGFs) are the key mediators of angiogenesis, we investigated feasibility and efficacy of local gene therapy for ISR utilizing soluble decoy VEGF receptors to reduce biological activity of adventitial VEGFs. Method Sixty-nine adult WHHL rabbit aortas were subjected to endothelial denudation. Six weeks later catheter-mediated local intramural infusion of 1.5x10e10 pfu adenoviruses encoding soluble VEGF Receptor-1 (sVEGFR1), sVEGFR2, sVEGFR3 or control LacZ and bare metal stent implantation were performed in the same aortic segment. Marker protein expression was assessed at 6d in LacZ cohort. Immunohistochemistry, morphometrical analyses and angiography were performed at d14, d42 and d90. Results: Transgene expression was localized to adventitia. All decoy receptors reduced the size of vasa-vasorum at 14d, AdsVEGFR2 animals also had reduced density of adventitial vasa-vasorum, whereas AdsVEGFR3 increased the density of vasa-vasorum. At d42, AdsVEGFR1 and AdsVEGFR2 reduced ISR (15.7 +/- 6.9% stenosis, P <0.01 and 16.5 +/- 2.7%, P <0.05, respectively) vs. controls (28.3 +/- 7.6%). Moreover, AdsVEGFR-3 treatment led to a non-significant trend in the reduction of adventitial lymphatics at all time points and these animals had significantly more advanced neointimal atherosclerosis at 14d and 42d vs. control animals. Conclusions: Targeting adventitial neovascularization using sVEGFR1 and sVEGFR2 is a novel strategy to reduce ISR. The therapeutic effects dissipate at late follow up following short expression profile of adenoviral vectors. However, inhibition of VEGFR3 signaling accelerates neoatherosclerosis.
Subject: In-stent restenosis
Gene therapy
Plaque angiogenesis
3121 General medicine, internal medicine and other clinical medicine
1182 Biochemistry, cell and molecular biology
Peer reviewed: Yes
Usage restriction: openAccess
Self-archived version: publishedVersion

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