Galina Wirth, Greta Juusola, Hanne Laakso, Nihay Laham-Karam, Seppo Ylä-Herttuala, Petra Korpisalo
{"title":"血管生成基因治疗诱导的持续毛细血管扩张不支持高脂血症小鼠缺血后肌肉恢复。","authors":"Galina Wirth, Greta Juusola, Hanne Laakso, Nihay Laham-Karam, Seppo Ylä-Herttuala, Petra Korpisalo","doi":"10.3389/fbioe.2025.1512962","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>AdVEGF or AdLacZ-control vector were delivered into the calf muscles of aged, hyperlipidemic LDLR<sup>-/-</sup>ApoB<sup>100/100</sup> 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.</p><p><strong>Results: </strong>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<sup>-/-</sup>ApoB<sup>100/100</sup> 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).</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":12444,"journal":{"name":"Frontiers in Bioengineering and Biotechnology","volume":"13 ","pages":"1512962"},"PeriodicalIF":4.8000,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12149096/pdf/","citationCount":"0","resultStr":"{\"title\":\"Sustained capillary enlargement induced by angiogenic gene therapy does not support post-ischemic muscle recovery of hyperlipidemic mice.\",\"authors\":\"Galina Wirth, Greta Juusola, Hanne Laakso, Nihay Laham-Karam, Seppo Ylä-Herttuala, Petra Korpisalo\",\"doi\":\"10.3389/fbioe.2025.1512962\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>AdVEGF or AdLacZ-control vector were delivered into the calf muscles of aged, hyperlipidemic LDLR<sup>-/-</sup>ApoB<sup>100/100</sup> 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.</p><p><strong>Results: </strong>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<sup>-/-</sup>ApoB<sup>100/100</sup> 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).</p><p><strong>Conclusion: </strong>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.</p>\",\"PeriodicalId\":12444,\"journal\":{\"name\":\"Frontiers in Bioengineering and Biotechnology\",\"volume\":\"13 \",\"pages\":\"1512962\"},\"PeriodicalIF\":4.8000,\"publicationDate\":\"2025-05-27\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12149096/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Frontiers in Bioengineering and Biotechnology\",\"FirstCategoryId\":\"5\",\"ListUrlMain\":\"https://doi.org/10.3389/fbioe.2025.1512962\",\"RegionNum\":3,\"RegionCategory\":\"工程技术\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/1/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q1\",\"JCRName\":\"BIOTECHNOLOGY & APPLIED MICROBIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Frontiers in Bioengineering and Biotechnology","FirstCategoryId":"5","ListUrlMain":"https://doi.org/10.3389/fbioe.2025.1512962","RegionNum":3,"RegionCategory":"工程技术","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/1/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"BIOTECHNOLOGY & APPLIED MICROBIOLOGY","Score":null,"Total":0}
Sustained capillary enlargement induced by angiogenic gene therapy does not support post-ischemic muscle recovery of hyperlipidemic mice.
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-/-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.
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-/-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).
Conclusion: 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.
期刊介绍：
The translation of new discoveries in medicine to clinical routine has never been easy. During the second half of the last century, thanks to the progress in chemistry, biochemistry and pharmacology, we have seen the development and the application of a large number of drugs and devices aimed at the treatment of symptoms, blocking unwanted pathways and, in the case of infectious diseases, fighting the micro-organisms responsible. However, we are facing, today, a dramatic change in the therapeutic approach to pathologies and diseases. Indeed, the challenge of the present and the next decade is to fully restore the physiological status of the diseased organism and to completely regenerate tissue and organs when they are so seriously affected that treatments cannot be limited to the repression of symptoms or to the repair of damage. This is being made possible thanks to the major developments made in basic cell and molecular biology, including stem cell science, growth factor delivery, gene isolation and transfection, the advances in bioengineering and nanotechnology, including development of new biomaterials, biofabrication technologies and use of bioreactors, and the big improvements in diagnostic tools and imaging of cells, tissues and organs.
In today`s world, an enhancement of communication between multidisciplinary experts, together with the promotion of joint projects and close collaborations among scientists, engineers, industry people, regulatory agencies and physicians are absolute requirements for the success of any attempt to develop and clinically apply a new biological therapy or an innovative device involving the collective use of biomaterials, cells and/or bioactive molecules. “Frontiers in Bioengineering and Biotechnology” aspires to be a forum for all people involved in the process by bridging the gap too often existing between a discovery in the basic sciences and its clinical application.
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