Sustained capillary enlargement induced by angiogenic gene therapy does not support post-ischemic muscle recovery of hyperlipidemic mice
BackgroundHyperlipidemia 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 thro...
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Frontiers Media S.A.
2025-05-01
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fbioe.2025.1512962/full |
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| author | Galina Wirth Galina Wirth Greta Juusola Greta Juusola Hanne Laakso Nihay Laham-Karam Seppo Ylä-Herttuala Seppo Ylä-Herttuala Petra Korpisalo Petra Korpisalo |
| author_facet | Galina Wirth Galina Wirth Greta Juusola Greta Juusola Hanne Laakso Nihay Laham-Karam Seppo Ylä-Herttuala Seppo Ylä-Herttuala Petra Korpisalo Petra Korpisalo |
| author_sort | Galina Wirth |
| collection | DOAJ |
| description | BackgroundHyperlipidemia 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.MethodsAdVEGF or AdLacZ-control vector were delivered into the calf muscles of aged, hyperlipidemic LDLR−/−ApoB100/100 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.ResultsIt 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−/−ApoB100/100 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 VEGF-induced 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).ConclusionHyperlipidemia 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. |
| format | Article |
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| institution | OA Journals |
| issn | 2296-4185 |
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| publishDate | 2025-05-01 |
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| spelling | doaj-art-bf7d68a1ee5a48a5a033e5224dd3b1b02025-08-20T02:29:19ZengFrontiers Media S.A.Frontiers in Bioengineering and Biotechnology2296-41852025-05-011310.3389/fbioe.2025.15129621512962Sustained capillary enlargement induced by angiogenic gene therapy does not support post-ischemic muscle recovery of hyperlipidemic miceGalina Wirth0Galina Wirth1Greta Juusola2Greta Juusola3Hanne Laakso4Nihay Laham-Karam5Seppo Ylä-Herttuala6Seppo Ylä-Herttuala7Petra Korpisalo8Petra Korpisalo9Heart Center, Kuopio University Hospital, Kuopio, FinlandA. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, FinlandHeart Center, Kuopio University Hospital, Kuopio, FinlandA. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, FinlandA. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, FinlandA. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, FinlandHeart Center, Kuopio University Hospital, Kuopio, FinlandA. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, FinlandHeart Center, Kuopio University Hospital, Kuopio, FinlandA. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, FinlandBackgroundHyperlipidemia 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.MethodsAdVEGF or AdLacZ-control vector were delivered into the calf muscles of aged, hyperlipidemic LDLR−/−ApoB100/100 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.ResultsIt 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−/−ApoB100/100 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 VEGF-induced 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).ConclusionHyperlipidemia 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.https://www.frontiersin.org/articles/10.3389/fbioe.2025.1512962/fullhyperlipidemiaischemiaadenovirusVEGFgene therapycapillary enlargement |
| spellingShingle | Galina Wirth Galina Wirth Greta Juusola Greta Juusola Hanne Laakso Nihay Laham-Karam Seppo Ylä-Herttuala Seppo Ylä-Herttuala Petra Korpisalo Petra Korpisalo Sustained capillary enlargement induced by angiogenic gene therapy does not support post-ischemic muscle recovery of hyperlipidemic mice Frontiers in Bioengineering and Biotechnology hyperlipidemia ischemia adenovirus VEGF gene therapy capillary enlargement |
| title | Sustained capillary enlargement induced by angiogenic gene therapy does not support post-ischemic muscle recovery of hyperlipidemic mice |
| title_full | Sustained capillary enlargement induced by angiogenic gene therapy does not support post-ischemic muscle recovery of hyperlipidemic mice |
| title_fullStr | Sustained capillary enlargement induced by angiogenic gene therapy does not support post-ischemic muscle recovery of hyperlipidemic mice |
| title_full_unstemmed | Sustained capillary enlargement induced by angiogenic gene therapy does not support post-ischemic muscle recovery of hyperlipidemic mice |
| title_short | Sustained capillary enlargement induced by angiogenic gene therapy does not support post-ischemic muscle recovery of hyperlipidemic mice |
| title_sort | sustained capillary enlargement induced by angiogenic gene therapy does not support post ischemic muscle recovery of hyperlipidemic mice |
| topic | hyperlipidemia ischemia adenovirus VEGF gene therapy capillary enlargement |
| url | https://www.frontiersin.org/articles/10.3389/fbioe.2025.1512962/full |
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