Adenoviral Gene Transfer of Gremlin Modulates Vascular Endothelial Growth Factor-A-Induced Angiogenesis in Porcine Myocardium

Coronary artery disease is a major cause of death and disability worldwide. New therapies are needed for patients who do not benefit or are not suitable for current treatments. Angiogenic gene therapy using vascular endothelial growth factors (VEGFs) has shown potential in preclinical trials. However, undesired side effects, such as increased permeability, limit their therapeutic potential. The aim of this study was to investigate if adenoviral gene transfer of a VEGF receptor 2 (VEGFR-2) ligand Gremlin, given simultaneously with VEGF-A, could modulate VEGFR-2-mediated increase in permeability without impairing the angiogenic effect of VEGF-A gene therapy. Gene transfers were done in pigs (n = 22) using endocardial injections with an endovascular injection catheter. Animals were divided in three groups receiving adenoviral (Ad) VEGF-A (n = 10), Gremlin (n = 6), or VEGF-A+Gremlin (n = 6) gene therapy. Animals were sacrificed and samples collected 6 days later for histological, safety, and permeability analyses. The mean capillary area was significantly increased in both treatment groups with AdVEGF-A when compared with the AdGremlin group. Also, the capillary area was significantly larger in AdVEGF-A group without AdGremlin. No significant differences in tissue permeability were observed using modified Miles assay between AdVEGF-A and AdVEGF-A+AdGremlin groups. However, cardiac tamponade and sudden cardiac deaths were observed only in the AdVEGF-A group. AdVEGF-A induces strong angiogenesis in porcine myocardium. Our results suggest that AdGremlin can limit the side effects of AdVEGF-A therapy, even though no direct effect on tissue permeability could be demonstrated. This could enable the use of larger AdVEGF-A doses to increase the treatment area and angiogenic effects without adverse side effects.

Medienart:

E-Artikel

Erscheinungsjahr:

2020

Erschienen:

2020

Enthalten in:

Zur Gesamtaufnahme - volume:31

Enthalten in:

Human gene therapy - 31(2020), 3-4 vom: 10. Feb., Seite 211-218

Sprache:

Englisch

Beteiligte Personen:

Pajula, Juho J [VerfasserIn]
Halonen, Paavo J [VerfasserIn]
Hätinen, Olli-Pekka [VerfasserIn]
Ylä-Herttuala, Seppo [VerfasserIn]
Nurro, Jussi [VerfasserIn]

Links:

Volltext

Themen:

Angiogenesis
Chronic ischemic heart disease
GREM1 protein, human
Gene therapy
Intercellular Signaling Peptides and Proteins
Journal Article
Research Support, Non-U.S. Gov't
Vascular Endothelial Growth Factor A

Anmerkungen:

Date Completed 03.06.2021

Date Revised 03.06.2021

published: Print-Electronic

Citation Status MEDLINE

doi:

10.1089/hum.2019.229

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM304848255