Vascular repair mechanisms : experimental, physiological and clinical studies
Author: Razuvajev, Anton
Date: 2009-06-04
Location: Thoraxklinikernas föreläsningssal, Karolinska Universitetssjukhuset
Time: 09.00
Department: Institutionen för molekylär medicin och kirurgi / Department of Molecular Medicine and Surgery
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Thesis (1001.Kb)
Abstract
Cardiovascular disease is the leading cause of global mortality and physical disability mainly due to the complications of atherothrombosis such as myocardial infarction or stroke. Surgical treatment directed to prevent this conditions is limited by the extensive healing response, intimal hyperplasia. Physiological healing reaction takes place in the diseased vessel wall aimed to repair the vessel after an injury, noxious stimuli or altered physical forces. It plays a central role in such diverse conditions as in the formation of the fibrous cap in atherogenesis, in the repair of vulnerable lesions after plaque rupture, in restenosis after arterial interventions, in venous bypass grafts.
In this thesis we investigated the mechanisms of vessel wall repair in various models. Molecular mechanisms involved in intimal hyperplasia were studied with a focus on the role of IGF-1 in SMC proliferation. Pharmacotherapy specifically targeting the IGF-l axis attenuated intimal hyperplasia after balloon injury through inhibition of SMC proliferation. Not only molecular signals from blood but also physical forces reach SMCs especially those which form neointima.
We demonstrated that increased levels of shear stress downregulate SMC proliferation and significantly alter gene expression. Tissue factor pathway inhibitor 2 is strongly upregulated by fluid shear stress in SMCs and can inhibit proliferation of both ECs and SMCs. This implies that hemodynamic forces can directly effect SMC gene expression and inthis way regulate intimal repair.
We evaluated non-invasive ultrasound biomicroscopy technique and found it sufficient to accurately monitor the healing reaction of the injured artery and to assess an effect of pharmacological inhibition of neointima formation. On human atherosclerotic lesions expression of a limited number of genes previously described to be involved in plaque stability were analyzed with respect to clinical variables assumed to reflect lesion phenotype. We showed that symptoms, statin treatment, and ultrasound morphology were clinical markers of plaque stability while time between the last qualifying symptom and surgery would characterize patterns of plaque healing.
By increasing our understanding of the molecular pathways that regulate vessel wall repair, we can develop pharmacological methods to control SMC activation and proliferation to improve outcome after vascular surgery. Additionally, the ability to pharmacologically regulate vessel wall healing could provide possibilities to combat plaque instability and prevent the clinical consequences of atherothrombosis.
In this thesis we investigated the mechanisms of vessel wall repair in various models. Molecular mechanisms involved in intimal hyperplasia were studied with a focus on the role of IGF-1 in SMC proliferation. Pharmacotherapy specifically targeting the IGF-l axis attenuated intimal hyperplasia after balloon injury through inhibition of SMC proliferation. Not only molecular signals from blood but also physical forces reach SMCs especially those which form neointima.
We demonstrated that increased levels of shear stress downregulate SMC proliferation and significantly alter gene expression. Tissue factor pathway inhibitor 2 is strongly upregulated by fluid shear stress in SMCs and can inhibit proliferation of both ECs and SMCs. This implies that hemodynamic forces can directly effect SMC gene expression and inthis way regulate intimal repair.
We evaluated non-invasive ultrasound biomicroscopy technique and found it sufficient to accurately monitor the healing reaction of the injured artery and to assess an effect of pharmacological inhibition of neointima formation. On human atherosclerotic lesions expression of a limited number of genes previously described to be involved in plaque stability were analyzed with respect to clinical variables assumed to reflect lesion phenotype. We showed that symptoms, statin treatment, and ultrasound morphology were clinical markers of plaque stability while time between the last qualifying symptom and surgery would characterize patterns of plaque healing.
By increasing our understanding of the molecular pathways that regulate vessel wall repair, we can develop pharmacological methods to control SMC activation and proliferation to improve outcome after vascular surgery. Additionally, the ability to pharmacologically regulate vessel wall healing could provide possibilities to combat plaque instability and prevent the clinical consequences of atherothrombosis.
List of papers:
I. Razuvaev A, Henderson B, Girnita L, Larsson O, Axelson M, Hedin U, Roy J (2007). The cyclolignan picropodophyllin attenuates intimal hyperplasia after rat carotid balloon injury by blocking insulin-like growth factor-1 receptor signaling. J Vasc Surg. 46(1): 108-15
Pubmed
II. Razuvaev A, Lund K, Roy J, Hedin U, Caidahl K (2008). Noninvasive real-time imaging of intima thickness after rat carotid artery balloon injury using ultrasound biomicroscopy. Atherosclerosis. 199(2): 310-6. Epub 2008 Jan 10
Pubmed
III. Razuvaev A, Ekstrand J, Folkersen L, Marcus D, Swedenborg J, Hansson G, Gabrielsen A, Paulsson-Berne G, Roy J, Hedin U (2009). Correlations between clinical variables and gene expression profiles in carotid plaque instability. [Manuscript]
IV. Ekstrand J, Razuvaev A, Roy J, Hedin U (2009). Expression of issue factor pathway inhibitor 2 is induced by fluid shear stress in vascular smooth muscle cells. [Manuscript]
I. Razuvaev A, Henderson B, Girnita L, Larsson O, Axelson M, Hedin U, Roy J (2007). The cyclolignan picropodophyllin attenuates intimal hyperplasia after rat carotid balloon injury by blocking insulin-like growth factor-1 receptor signaling. J Vasc Surg. 46(1): 108-15
Pubmed
II. Razuvaev A, Lund K, Roy J, Hedin U, Caidahl K (2008). Noninvasive real-time imaging of intima thickness after rat carotid artery balloon injury using ultrasound biomicroscopy. Atherosclerosis. 199(2): 310-6. Epub 2008 Jan 10
Pubmed
III. Razuvaev A, Ekstrand J, Folkersen L, Marcus D, Swedenborg J, Hansson G, Gabrielsen A, Paulsson-Berne G, Roy J, Hedin U (2009). Correlations between clinical variables and gene expression profiles in carotid plaque instability. [Manuscript]
IV. Ekstrand J, Razuvaev A, Roy J, Hedin U (2009). Expression of issue factor pathway inhibitor 2 is induced by fluid shear stress in vascular smooth muscle cells. [Manuscript]
Issue date: 2009-05-14
Rights:
Publication year: 2009
ISBN: 978-91-7409-520-3
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