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Article ; Online: Capillary Dynamics Regulate Post-Ischemic Muscle Damage and Regeneration in Experimental Hindlimb Ischemia.

Wirth, Galina / Juusola, Greta / Tarvainen, Santeri / Laakkonen, Johanna P / Korpisalo, Petra / Ylä-Herttuala, Seppo

2023 Volume 12, Issue 16

Abstract: This study aimed to show the significance of capillary function in post-ischemic recovery from the perspective of physiological parameters, such as blood flow, hemoglobin oxygenation and tissue regeneration. Muscle-level microvascular alterations of ... ...

Abstract	This study aimed to show the significance of capillary function in post-ischemic recovery from the perspective of physiological parameters, such as blood flow, hemoglobin oxygenation and tissue regeneration. Muscle-level microvascular alterations of blood flow and hemoglobin oxygenation, and post-ischemic myofiber and capillary responses were analyzed in aged, healthy C57Bl/6J mice (
MeSH term(s)	Animals ; Mice ; Ischemia ; Arteries ; Endothelium, Vascular ; Mice, Inbred C57BL ; Muscles ; Hindlimb
Language	English
Publishing date	2023-08-14
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells12162060
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Article ; Online: Angiogenic gene therapy in cardiovascular diseases: dream or vision?

Ylä-Herttuala, Seppo / Bridges, Charles / Katz, Michael G / Korpisalo, Petra

European heart journal

2017 Volume 38, Issue 18, Page(s) 1365–1371

Abstract: Chronic cardiovascular diseases are significant health problems. Although current treatment strategies have tremendously improved disease management, up to 30% of these patients cannot be successfully treated with current treatment approaches and new ... ...

Abstract	Chronic cardiovascular diseases are significant health problems. Although current treatment strategies have tremendously improved disease management, up to 30% of these patients cannot be successfully treated with current treatment approaches and new treatment strategies are clearly needed. Gene therapy and therapeutic vascular growth may provide a new treatment option for these patients. Several growth factors, like vascular endothelial growth factors, fibroblast growth factors and hepatocyte growth factor have been tested in clinical trials. However, apart from demonstration of increased vascularity, very few results with clinical significance have been obtained. Problems with gene transfer efficiency, short duration of transgene expression, selection of endpoints, and suboptimal patients for gene therapy have been recognized. Ongoing gene therapy trials have included improvements in study protocols, vector delivery and endpoints, addressing the identified problems. Better, targeted delivery systems and new, more optimal growth factors have been taken to clinical testing. Recent advances in these areas will be discussed and the concept of angiogenic therapy as a sole treatment is re-evaluated. A combination with regenerative therapies or standard revascularization operations might be needed to improve tissue function and clinical benefits.
MeSH term(s)	Angiogenesis Inducing Agents/therapeutic use ; Cardiovascular Diseases/therapy ; Clinical Trials as Topic ; Forecasting ; Gene Transfer Techniques ; Genetic Therapy/methods ; Genetic Vectors ; Heart Failure/therapy ; Humans ; Myocardial Ischemia/therapy ; Patient Selection ; Peripheral Vascular Diseases/therapy ; Vascular Endothelial Growth Factors/genetics
Chemical Substances	Angiogenesis Inducing Agents ; Vascular Endothelial Growth Factors
Language	English
Publishing date	2017-01-09
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	603098-1
ISSN	1522-9645 ; 0195-668X
ISSN (online)	1522-9645
ISSN	0195-668X
DOI	10.1093/eurheartj/ehw547
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Article ; Online: Stimulation of functional vessel growth by gene therapy.

Korpisalo, Petra / Ylä-Herttuala, Seppo

Integrative biology : quantitative biosciences from nano to macro

2010 Volume 2, Issue 2-3, Page(s) 102–112

Abstract: The process of growing new blood vessels through gene therapy may be difficult but is certainly possible. This review will discuss the most important factors determining the efficacy of angiogenic gene therapy. ...

Abstract	The process of growing new blood vessels through gene therapy may be difficult but is certainly possible. This review will discuss the most important factors determining the efficacy of angiogenic gene therapy.
MeSH term(s)	Animals ; Blood Vessels/growth & development ; Genetic Therapy/trends ; Humans ; Neovascularization, Physiologic/physiology ; Tissue Engineering/trends
Language	English
Publishing date	2010-03
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2480063-6
ISSN	1757-9708 ; 1757-9694
ISSN (online)	1757-9708
ISSN	1757-9694
DOI	10.1039/b921869f
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Article ; Online: Efficacy and Safety of Clinical-Grade Human Vascular Endothelial Growth Factor-D

Leikas, Aleksi J / Laham-Karam, Nihay / Agtereek, Eline / Peltonen, Hanna M / Selander, Tuomas / Korpisalo, Petra / Holappa, Lari / Hartikainen, Juha E K / Heikura, Tommi / Ylä-Herttuala, Seppo

Human gene therapy

2021 Volume 32, Issue 13-14, Page(s) 761–770

Abstract: Biological bypass through induced angiogenesis by vascular endothelial growth factor D (VEGF-D) gene therapy (GT) is a new concept for the treatment of cardiac ischemia. Serotype 5 adenoviruses are used in the clinical trials for transferring the VEGF-D ... ...

Abstract	Biological bypass through induced angiogenesis by vascular endothelial growth factor D (VEGF-D) gene therapy (GT) is a new concept for the treatment of cardiac ischemia. Serotype 5 adenoviruses are used in the clinical trials for transferring the VEGF-D cDNA into the ischemic myocardium. However, the presence of replication-competent vectors in the adenovirus products is a widely recognized problem that may pose a potential safety risk to the treated patients. We compared three different VEGF-D GT production lots containing different levels of replication-competent adenoviruses (RCA) tested in 3 × 10
MeSH term(s)	Adenoviridae/genetics ; Adenoviridae/metabolism ; Adenoviruses, Human ; Animals ; Genetic Therapy ; Genetic Vectors/genetics ; Humans ; Neovascularization, Pathologic ; Rabbits ; Tissue Distribution ; Vascular Endothelial Growth Factor D/genetics ; Vascular Endothelial Growth Factor D/metabolism
Chemical Substances	Vascular Endothelial Growth Factor D
Language	English
Publishing date	2021-03-04
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1028152-6
ISSN	1557-7422 ; 1043-0342
ISSN (online)	1557-7422
ISSN	1043-0342
DOI	10.1089/hum.2020.299
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Article ; Online: Critical limb-threatening ischaemia and microvascular transformation: clinical implications.

European heart journal

2023 Volume 45, Issue 4, Page(s) 255–264

Abstract: Background and aims: Clinical management of critical limb-threatening ischaemia (CLTI) is focused on prevention and treatment of atherosclerotic arterial occlusions. The role of microvascular pathology in disease progression is still largely unspecified ...

Abstract	Background and aims: Clinical management of critical limb-threatening ischaemia (CLTI) is focused on prevention and treatment of atherosclerotic arterial occlusions. The role of microvascular pathology in disease progression is still largely unspecified and more importantly not utilized for treatment. The aim of this explorative study was to characterize the role of the microvasculature in CLTI pathology. Methods: Clinical high-resolution imaging of CLTI patients (n = 50) and muscle samples from amputated CLTI limbs (n = 40) were used to describe microvascular pathology of CLTI at the level of resting muscle blood flow and microvascular structure, respectively. Furthermore, a chronic, low arterial driving pressure-simulating ischaemia model in rabbits (n = 24) was used together with adenoviral vascular endothelial growth factor A gene transfers to study the effect of microvascular alterations on muscle outcome. Results: Resting microvascular blood flow was not depleted but displayed decreased capillary transit time (P < .01) in CLTI muscles. Critical limb-threatening ischaemia muscle microvasculature also exhibited capillary enlargement (P < .001) and further arterialization along worsening of myofibre atrophy and detaching of capillaries from myofibres. Furthermore, CLTI-like capillary transformation was shown to worsen calf muscle force production (P < .05) and tissue outcome (P < .01) under chronic ischaemia in rabbits and in healthy, normal rabbit muscle. Conclusions: These findings depict a progressive, hypoxia-driven transformation of the microvasculature in CLTI muscles, which pathologically alters blood flow dynamics and aggravates tissue damage under low arterial driving pressure. Hypoxia-driven capillary enlargement can be highly important for CLTI outcomes and should therefore be considered in further development of diagnostics and treatment of CLTI.
MeSH term(s)	Humans ; Rabbits ; Animals ; Peripheral Arterial Disease/therapy ; Risk Factors ; Vascular Endothelial Growth Factor A ; Ischemia ; Hypoxia ; Treatment Outcome ; Retrospective Studies ; Chronic Disease
Chemical Substances	Vascular Endothelial Growth Factor A
Language	English
Publishing date	2023-08-25
Publishing country	England
Document type	Journal Article
ZDB-ID	603098-1
ISSN	1522-9645 ; 0195-668X
ISSN (online)	1522-9645
ISSN	0195-668X
DOI	10.1093/eurheartj/ehad562
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Article ; Online: Improved endothelialization of small-diameter ePTFE vascular grafts through growth factor therapy.

Hytönen, Jarkko P / Leppänen, Olli / Taavitsainen, Jouni / Korpisalo, Petra / Laidinen, Svetlana / Alitalo, Kari / Wadström, Jonas / Rissanen, Tuomas T / Ylä-Herttuala, Seppo

Vascular biology (Bristol, England)

2019 Volume 1, Issue 1, Page(s) 1–9

Abstract: Background: Prosthetic vascular grafts in humans characteristically lack confluent endothelialization regardless of the duration of implantation. Use of high-porosity grafts has been proposed as a way to induce endothelialization through transgraft ... ...

Abstract	Background: Prosthetic vascular grafts in humans characteristically lack confluent endothelialization regardless of the duration of implantation. Use of high-porosity grafts has been proposed as a way to induce endothelialization through transgraft capillarization, although early experiments failed to show increased healing in man. Objectives: We hypothesized that transduction of tissues around the prosthetic conduit with vectors encoding VEGF receptor-2 (VEGFR2) ligands would augment transinterstitial capillarization and induce luminal endothelialization of high-porosity ePTFE grafts. Methods: Fifty-two NZW rabbits received 87 ePTFE uni- or bilateral end-to-end interposition grafts in carotid arteries. Rabbits were randomized to local therapy with adenoviruses encoding AdVEGF-A165, AdVEGF-A109 or control AdLacZ and analyzed at 6 and 28 days after surgery by contrast-enhanced ultrasound and histology. Results: AdVEGF-A165 and AdVEGF-A109 dramatically increased perfusion in perigraft tissues at 6 days (14.2 ± 3.6 or 16.7 ± 2.6-fold increases, Conclusions: This study suggests that transient local overexpression of VEGFR2 ligands in the peri-implant tissues at the time of graft implantation is a novel strategy to increase endothelialization of high-porosity ePTFE vascular grafts and improve the patency of small-diameter vascular prostheses.
Language	English
Publishing date	2019-01-03
Publishing country	England
Document type	Journal Article
ISSN	2516-5658
ISSN (online)	2516-5658
DOI	10.1530/VB-18-0001
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Article: Stimulation of functional vessel growth by gene therapy

Korpisalo, Petra / Ylä-Herttuala, Seppo

Integrative biology. 2010 Mar. 5, v. 2, no. 2-3

2010

Abstract	The process of growing new blood vessels through gene therapy may be difficult but is certainly possible. This review will discuss the most important factors determining the efficacy of angiogenic gene therapy.
Keywords	angiogenesis ; blood vessels ; gene therapy
Language	English
Dates of publication	2010-0305
Size	p. 102-112.
Publishing place	The Royal Society of Chemistry
Document type	Article
ZDB-ID	2480063-6
ISSN	1757-9708 ; 1757-9694
ISSN (online)	1757-9708
ISSN	1757-9694
DOI	10.1039/b921869f
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Article ; Online: Promoting blood vessel growth in ischemic diseases: challenges in translating preclinical potential into clinical success.

Dragneva, Galina / Korpisalo, Petra / Ylä-Herttuala, Seppo

Disease models & mechanisms

2013 Volume 6, Issue 2, Page(s) 312–322

Abstract: Angiogenic therapy, which involves the use of an exogenous stimulus to promote blood vessel growth, is an attractive approach for the treatment of ischemic diseases. It has been shown in animal models that the stimulation of blood vessel growth leads to ... ...

Abstract	Angiogenic therapy, which involves the use of an exogenous stimulus to promote blood vessel growth, is an attractive approach for the treatment of ischemic diseases. It has been shown in animal models that the stimulation of blood vessel growth leads to the growth of the whole vascular tree, improvement of ischemic tissue perfusion and improved muscle aerobic energy metabolism. However, very few positive results have been gained from Phase 2 and 3 clinical angiogenesis trials. Many reasons have been given for the failures of clinical trials, including poor transgene expression (in gene-therapy trials) and instability of the vessels induced by therapy. In this Review, we discuss the selection of preclinical models as one of the main reasons why clinical translation has been unsuccessful thus far. This issue has received little attention, but could have had dramatic implications on the expectations of clinical trials. We highlight crucial differences between human patients and animal models with regards to blood flow and pressure, as well as issues concerning the chronic nature of ischemic diseases in humans. We use these as examples to demonstrate why the results from preclinical trials might have overestimated the efficacy of angiogenic therapies developed to date. We also suggest ways in which currently available animal models of ischemic disease could be improved to better mimic human disease conditions, and offer advice on how to work with existing models to avoid overestimating the efficacy of new angiogenic therapies.
MeSH term(s)	Angiogenesis Inducing Agents/pharmacology ; Angiogenesis Inducing Agents/therapeutic use ; Animals ; Blood Vessels/drug effects ; Blood Vessels/growth & development ; Disease Models, Animal ; Humans ; Ischemia/drug therapy ; Ischemia/pathology ; Neovascularization, Physiologic/drug effects ; Translational Medical Research
Chemical Substances	Angiogenesis Inducing Agents
Language	English
Publishing date	2013-02-08
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2451104-3
ISSN	1754-8411 ; 1754-8403
ISSN (online)	1754-8411
ISSN	1754-8403
DOI	10.1242/dmm.010413
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Article ; Online: T

Laakso, Hanne / Wirth, Galina / Korpisalo, Petra / Ylä-Herttuala, Elias / Michaeli, Shalom / Ylä-Herttuala, Seppo / Liimatainen, Timo

NMR in biomedicine

2018 Volume 31, Issue 5, Page(s) e3909

Abstract: The identification of areas with regenerative potential in ischemic tissues would allow the targeting of treatments supporting tissue recovery. The regeneration process involves the activation of several cellular and molecular responses which could be ... ...

Abstract	The identification of areas with regenerative potential in ischemic tissues would allow the targeting of treatments supporting tissue recovery. The regeneration process involves the activation of several cellular and molecular responses which could be detected using magnetic resonance imaging (MRI). However, to date, magnetic resonance (MR) relaxation parameters have received little attention in the diagnosis and follow-up of limb ischemia. The purpose of this study was to evaluate the feasibility of different MRI relaxation and diffusion tensor imaging parameters in the detection of areas showing early signs of regeneration in ischemic mouse skeletal muscles. T
MeSH term(s)	Animals ; Diffusion Tensor Imaging ; Female ; Ischemia/diagnostic imaging ; Ischemia/pathology ; Mice ; Muscle, Skeletal/blood supply ; Muscle, Skeletal/diagnostic imaging ; Muscle, Skeletal/pathology ; Regeneration ; Time Factors
Language	English
Publishing date	2018-03-23
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1000976-0
ISSN	1099-1492 ; 0952-3480
ISSN (online)	1099-1492
ISSN	0952-3480
DOI	10.1002/nbm.3909
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Zs.A 2869: Show issues

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Article ; Online: Perivascular Macrophages Regulate Blood Flow Following Tissue Damage.

Vågesjö, Evelina / Parv, Kristel / Ahl, David / Seignez, Cédric / Herrera Hidalgo, Carmen / Giraud, Antoine / Leite, Catarina / Korsgren, Olle / Wallén, Håkan / Juusola, Greta / Hakovirta, Harri H / Rundqvist, Helene / Essand, Magnus / Holm, Lena / Johnson, Randall S / Thålin, Charlotte / Korpisalo, Petra / Christoffersson, Gustaf / Phillipson, Mia

Circulation research

2021 Volume 128, Issue 11, Page(s) 1694–1707

Abstract: Figure: see text]. ...

Abstract	[Figure: see text].
MeSH term(s)	Animals ; Cell Movement ; Cell Proliferation ; Chemokine CCL2/metabolism ; Chemokine CXCL12/metabolism ; Humans ; Ischemia/physiopathology ; Ischemia/therapy ; Macrophages/cytology ; Macrophages/metabolism ; Macrophages/physiology ; Mice ; Muscle, Skeletal/blood supply ; Nitric Oxide/metabolism ; Nitric Oxide Synthase Type II/deficiency ; Nitric Oxide Synthase Type II/metabolism ; Nitric Oxide Synthase Type III/metabolism ; Plasmids/metabolism ; Receptors, CCR2/metabolism ; Receptors, CXCR4/metabolism ; Regional Blood Flow/physiology
Chemical Substances	Chemokine CCL2 ; Chemokine CXCL12 ; Receptors, CCR2 ; Receptors, CXCR4 ; Nitric Oxide (31C4KY9ESH) ; Nitric Oxide Synthase Type II (EC 1.14.13.39) ; Nitric Oxide Synthase Type III (EC 1.14.13.39)
Language	English
Publishing date	2021-04-21
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80100-8
ISSN	1524-4571 ; 0009-7330 ; 0931-6876
ISSN (online)	1524-4571
ISSN	0009-7330 ; 0931-6876
DOI	10.1161/CIRCRESAHA.120.318380
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