ORIGINAL RESEARCH article
Front. Bioeng. Biotechnol.
Sec. Cell and Gene Therapy
Volume 13 - 2025 | doi: 10.3389/fbioe.2025.1512962
This article is part of the Research TopicAngiogenic Therapies for Ischemic DiseaseView all articles
Sustained capillary enlargement induced by angiogenic gene therapy does not support post-ischemic muscle recovery of hyperlipidemic mice
Provisionally accepted
- 1Kuopio University Hospital, Kuopio, Finland
- 2University of Eastern Finland, Kuopio, Northern Savonia, Finland
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Background: Hyperlipidemia is known to impair endothelial function. We have recently shown that hyperlipidemia also blunts native post-ischemic capillary enlargement that is important for efficient skeletal muscle recovery from ischemia as it supports the recovery of arterial driving pressure and through intussusception increases capillary density. The correction of capillary reactivity under hyperlipidemia could, therefore, improve post-ischemic skeletal muscle recovery. This study tested the ability of adenoviral (Ad) vascular endothelial growth factor (VEGF) gene therapy to rescue capillary enlargement and improve post-ischemic muscle repair in hyperlipidemic mice.Methods: AdVEGF or AdLacZ-control vector were delivered into the calf muscles of aged, hyperlipidemic LDLR -/-ApoB 100/100 mice (n=58) after induction of acute ischemia. The effects of AdVEGF on capillary phenotype, tissue edema, restoration of blood flow parameters, microvascular hemoglobin oxygenation and tissue damage/regeneration were evaluated using immunohistological analyses, magnetic resonance imaging, contrast-enhanced ultrasound imaging, photoacoustic imaging and histological analyses, respectively, up to 29 days after induced ischemia and gene transfer.Results: It was found that AdVEGF gene therapy was able to promote capillary enlargement (P<0.05) that led to recovery of arterial driving pressure in ischemic LDLR -/-ApoB 100/100 muscles. However, capillary enlargement induced by AdVEGF in the hyperlipidemic mice was delayed, had a long-lasting effect (P<0.05) and did not promote intussusception. Instead, side-effects of VEGFinduced capillary enlargement, i.e., tissue edema (P<0.01) and subsequently delayed blood flow recovery (P<0.05), aggravated ischemic tissue damage (P<0.01).Hyperlipidemia or old age did not seem to impair AdVEGF-induced capillary enlargement. However, regarding the side-effects of capillary enlargement, therapies trying to promote post-ischemic skeletal muscle recovery through angiogenesis should consider not only capillary size or density but also timing and dynamics of the capillary changes.
Keywords: Hyperlipidemia, Ischemia, adenovirus, VEGF, Gene Therapy, capillary enlargement, muscle damage, Edema
Received: 17 Oct 2024; Accepted: 14 May 2025.
Copyright: © 2025 Wirth, Juusola, Laakso, Ylä-Herttuala and Korpisalo. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Petra Korpisalo, Kuopio University Hospital, Kuopio, Finland
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