Therapeutic myocardial angiogenesis and its pharmacological modulation
Author: Siddiqui, Anwar J
Date: 2005-10-21
Location: C1 87, Karolinska Universitetssjukhuset, Huddinge
Time: 9.00
Department: Institutionen för medicin, Huddinge Sjukhus / Department of Medicine at Huddinge University Hospital
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Thesis (3.982Mb)
Abstract
Angiogenesis is the formation of new blood vessels induced by the proliferation and migration of endothelial cells. Because angiogenesis is a complex process, therapeutic efficacy may be improved by overexpression of combined angiogenic factors. Angiogenic effects of a single factor phVEGF-A (V) / phAng-1 (A) or their combination (V+A) were investigated in the myocardium.
In the ischemic myocardium, phVEGF-A gene transfer alone increased myocardial capillary and arteriolar densities more than double and phAng-1 had a similar effect. Transient overexpression of VEGF-A boosts angiogenesis at the arteriolar level more than at the capillary level. Combination with Ang-1 further boosts this effect and induced up to a 7.5 fold increase in vessel growth. Overexpressed growth factors (V, A, and V+A) stimulated the mouse VEGF-Ang system whereas placebo plasmid had no such effects. Phosphorylation of antiapoptotic Akt and its downstream effector GSK3-alpha/beta were lower during myocardial ischemia and there was no difference between any of the treatments.
Upregulation of the endogenous ligands / receptors of the VEGF-angiopoietin system could be the mechanism for the therapeutic angiogenic booster effect during myocardial ischemia, a process that may occur independent of the Akt pathway. Hypercholesterolemia and aging are associated with impaired vascular density associated with downregulation of mVEGF, VEGFR- 1, VEGFR-2, eNOS, Akt and upregulation of apoptotic protein p38 MAPK phosphorylation. phVEGF gene transfer in combination with simvastatin corrected impaired vascularity concurrently with stimulation of the VEGF system, increased eNOS production and reduced p38 MAPK phosphorylation.
In the non-compromised heart enalapril and candesartan both specifically inhibit phVEGF-A induced myocardial angiogenesis associated with inhibition of hVEGF-A expression and decreased endogenous expression of the mVEGF ligand /receptor system. Combined overexpression of VEGF and angiopoietin has an angiogenic booster effect that occurs due to stimulation of the endogenous VEGF-Angiopoetin system. Aging and hypercholesterolemia have negative effects on angiogenesis. Commonly used cardiovascular drugs can stimulate or inhibit angiogenesis.
In the ischemic myocardium, phVEGF-A gene transfer alone increased myocardial capillary and arteriolar densities more than double and phAng-1 had a similar effect. Transient overexpression of VEGF-A boosts angiogenesis at the arteriolar level more than at the capillary level. Combination with Ang-1 further boosts this effect and induced up to a 7.5 fold increase in vessel growth. Overexpressed growth factors (V, A, and V+A) stimulated the mouse VEGF-Ang system whereas placebo plasmid had no such effects. Phosphorylation of antiapoptotic Akt and its downstream effector GSK3-alpha/beta were lower during myocardial ischemia and there was no difference between any of the treatments.
Upregulation of the endogenous ligands / receptors of the VEGF-angiopoietin system could be the mechanism for the therapeutic angiogenic booster effect during myocardial ischemia, a process that may occur independent of the Akt pathway. Hypercholesterolemia and aging are associated with impaired vascular density associated with downregulation of mVEGF, VEGFR- 1, VEGFR-2, eNOS, Akt and upregulation of apoptotic protein p38 MAPK phosphorylation. phVEGF gene transfer in combination with simvastatin corrected impaired vascularity concurrently with stimulation of the VEGF system, increased eNOS production and reduced p38 MAPK phosphorylation.
In the non-compromised heart enalapril and candesartan both specifically inhibit phVEGF-A induced myocardial angiogenesis associated with inhibition of hVEGF-A expression and decreased endogenous expression of the mVEGF ligand /receptor system. Combined overexpression of VEGF and angiopoietin has an angiogenic booster effect that occurs due to stimulation of the endogenous VEGF-Angiopoetin system. Aging and hypercholesterolemia have negative effects on angiogenesis. Commonly used cardiovascular drugs can stimulate or inhibit angiogenesis.
List of papers:
I. Siddiqui AJ, Blomberg P, Wardell E, Hellgren I, Eskandarpour M, Islam KB, Sylven C (2003). Combination of angiopoietin-1 and vascular endothelial growth factor gene therapy enhances arteriogenesis in the ischemic myocardium. Biochem Biophys Res Commun. 310(3): 1002-9.
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II. Siddiqui AJ, Gustafsson T, Widegren U, Grinnemo KH, Dellgren G, Hao X, Mansson-Broberg A, Fischer H, Sylven C (2005). Therapeutic endogenous ligand/receptor induction of the VEGF-angiopoietin system after intramyocardial gene transfer during myocardial ischemia. [Submitted]
III. Siddiqui AJ, Gustafsson T, Fischer H, Widegren U, Hao X, Mansson-Broberg A, Grinnemo KH, Dellgren G, Sylven C (2004). Simvastatin enhances myocardial angiogenesis induced by vascular endothelial growth factor gene transfer. J Mol Cell Cardiol. 37(6): 1235-44.
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Pubmed
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IV. Siddiqui AJ, Mansson-Broberg A, Gustafsson T, Grinnemo KH, Dellgren G, Hao X, Fischer H, Sylven C (2005). Antagonism of the renin angiotensin system counteracts cardiac angiogenic VEGF gene therapy. American Journal of Hypertension. 18: 1347-52.
Fulltext (DOI)
Pubmed
View record in Web of Science®
I. Siddiqui AJ, Blomberg P, Wardell E, Hellgren I, Eskandarpour M, Islam KB, Sylven C (2003). Combination of angiopoietin-1 and vascular endothelial growth factor gene therapy enhances arteriogenesis in the ischemic myocardium. Biochem Biophys Res Commun. 310(3): 1002-9.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Siddiqui AJ, Gustafsson T, Widegren U, Grinnemo KH, Dellgren G, Hao X, Mansson-Broberg A, Fischer H, Sylven C (2005). Therapeutic endogenous ligand/receptor induction of the VEGF-angiopoietin system after intramyocardial gene transfer during myocardial ischemia. [Submitted]
III. Siddiqui AJ, Gustafsson T, Fischer H, Widegren U, Hao X, Mansson-Broberg A, Grinnemo KH, Dellgren G, Sylven C (2004). Simvastatin enhances myocardial angiogenesis induced by vascular endothelial growth factor gene transfer. J Mol Cell Cardiol. 37(6): 1235-44.
Fulltext (DOI)
Pubmed
View record in Web of Science®
IV. Siddiqui AJ, Mansson-Broberg A, Gustafsson T, Grinnemo KH, Dellgren G, Hao X, Fischer H, Sylven C (2005). Antagonism of the renin angiotensin system counteracts cardiac angiogenic VEGF gene therapy. American Journal of Hypertension. 18: 1347-52.
Fulltext (DOI)
Pubmed
View record in Web of Science®
Issue date: 2005-09-30
Rights:
Publication year: 2005
ISBN: 91-7140-511-9
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