Veins are conduits for bypass surgery. Their mode of implantation is not ideal, which is reflected by the incidence of vein graft failures (20 - 40%). Little is known whether high flow, high shear stress can regress an established narrowing in the vasculature, which would be the same as a treatment of a developed vascular disease.
The majority of graft failures are caused by flow restricting stenosis and subsequent thrombosis within the first year. Low shear stress has been associated with increased scar tissue, intimal hyperplasia(IH) in experimental vein grafts and injured arteries. Experimental, epidemiologic and clinical studies have provided evidence that physical exercise has beneficial effects on the vascular structure. Exercise-induced increases in blood flow and high shear stress, have been observed to enhance vascular function and beneficial effects on cardiovascular remodeling. We wanted to test whether high flow, high shear stress can regress an established narrowing in the vasculature, which would be the same as a treatment for a developed vascular disease. As of today all clinical undertakings are either symptomatic or prophylactic but the underlying disease when established remains unchanged. To test our hypothesis a mouse model for bypass surgery has been etsablished as one of 5 centres in Europe (it is small structures !!) The mice underwent vein by-pass grafting of the common carotid artery. The vessel graft (the inferior caval vein) was harvested from a donor mouse and grafted to the right common carotid artery (CCA) in the recipient.
The operative change in flow was induced in two ways. Either by ligation of the contralateral carotid artery to induce a compensatory increase of blood flow through the ipsilateral carotid graft or by training. Training was imposed by running on a motor treadmill 5 days/week, with the training program 4x4, which means 4 minutes (with the 85-90% of max heart rate) repeated 4 times with 2 minutes of recovery (70 % of max heart rate).
A huge number of mice have been operated upon. The specimens have been analyzed with histology and functional genomics. The results are statistically significant yet surprising. Increased flow does not reduce established thickening in vein grafts in mice. Furthermore training that is performed under mental stress is in mice not beneficial. The mental stress has been judged from classical genes that increase under mental pressure and the results are different to valid control groups. All data is present and will be the base for 2 publications in international journals
Stenoses in the distal anastomosis of bypasses is very common (30 – 40%). The stenoses have a vascular wall biology that resemble atherosclerosis.
It seems as if increased flow can reduce such stenoses. Insights into the biology behind such a response can give us future possibilities to specific therapy that make them disappear.
We have from the money given, established, as one of four centres in Europe, an arterial bypass model in mice. A vein from a donor animal is inter positioned to the common carotid artery of a recipient. This is done with a cuff technique without any sutures. We have had international collaboration to have optimal training.
These bypasses get after 6 weeks a stenosis. At this time-point the bypasses have been subjected to increased flow by ligation of the contralateral carotid artery. To our joy the established stenoses reduced substantially after another 6 weeks(12 weeks altogether). The reduction is around 50%. As controls we have two groups euthanized at 6 and 12 weeks. This demonstrates that stenoses in the arterial tree can biologically be induced to decrease perhaps even to disappear.
Furthermore, one group has been subjected to training. The animals have been training one hour daily on a treadmill with a standardized speed. Training seems to stop further progress of the stenosis in the grafts but cannot reduce the narrowing that is present.
We have extracted mRNA from the veins. We will now with functional genomics investigate the signaling for this response. This will be done in collaboration with the FUGE platform. The FUGE analysis has economical support from another source.
The project is very promising !! The use of mice will give us the opportunity to use gene-modified animals in the future.
We expect to get 2 publications in a high ranked journal when the project is finished.