XII^th International Symposium on Atherosclerosis, Stockholm, Sweden. (June 25-29, 2000)

The overexpression of therapeutically important proteins and genes potentially offers new treatments for cardiovascular diseases.

Vascular gene transfer potentially offers new treatments for cardiovascular diseases. It can be used to overexpress therapeutically important proteins and correct genetic defects, and to test experimentally the effects of various genes in a local vascular compartment. One of the sessions of the Symposium focused on gene therapy approaches for angiogenesis stimulation in hischemic limb and myocardium, prevention of restenosis, the treatment of hyperlipidemia, and prevention of atherosclerotic lesion formation.

The vascular endothelial growth factor (VEGF) was the focus of more than one presentation. VEGF, possibly through a hypoxic stimulus, increases blood flow and promotes angiogenesis in the myocardium and in peripheral vessels, as assessed in several animal models of vascular insufficiency. VEGF is also implicated in vascular protection, possibly by stimulating the production of nitric oxide (NO) and prostacyclin. These two intercellular mediators exert several effects, besides vasodilation, including the inhibition of smooth muscle cells (SMC) proliferation, antiplatelet actions, and, in the case of NO, inhibition of leukocyte adhesion. Dr. S. Ylä-Herttuala (University of Kuopio, Finland) presented the results of adenovirus-mediated VEGF-C (a member of the VEGF family) gene transfer on neointima formation after endothelial denudation in rabbits. VEGF-C gene transfer significantly reduced intimal thickening (intima/media ratio of 0.38 versus 0.57 for control rabbits). These results suggest that VEGF-C gene therapy may be useful for the prevention of post-angioplasty restenosis and vessel wall thickening after vascular manipulation. Dr. Ylä-Herttuala also provided an update on an ongoing clinical study, conducted by his group, for the treatment of peripheral artery disease. Briefly, patients underwent percutaneus transluminal angioplasty (PTA), and subsequently the VEGF-A gene was infused at the PTA site, using either an adenoviral or a plasmid/liposome vector. Up to now, both therapies appear to be well tolerated and, particularly in the adenovirus VEGF-A-treated group, the presence of new blood vessels at the site of the infusion has been observed. The study will be completed in about one year.

The distinct signal transduction mechanisms by which VEGF stimulates an angiogenic response are not known. Morales-Ruiz et al. recently (Circ. Res. 2000; 86:892-896) demonstrated that the protein kinase Akt mediates some angiogenic effects of VEGF, such as increased NO production and endothelial cell survival and migration. Interestingly, Dr. K. Walsh (Tufts University, Boston, USA) showed that HMG-CoA reductase inhibitors, among their pleiotropic effects, are able to activate Akt, and to promote an angiogenic response. In fact, in a rabbit hindlimb model, simvastatin treatment displayed an angiogenic effect, similar to that observed with VEGF gene transfer.

Gene therapy could be also a powerful approach for the treatment of dyslipidemias and atherosclerosis prevention, if a long-term expression of the therapeutic genes can be achieved. Dr. L. Chan (Baylor College of Medicine, Houston, USA) delivered VLDL receptor, apolipoprotein (apo) A-I or apoE genes to the liver of FH (LDL receptor knock-out) mice, by using a novel adenoviral vector (helper-dependent adenovirus, HD-Ad). A single injection was sufficient to obtain high gene expression for up to six months, without significant toxicity. VLDL receptor and apoE gene therapies dramatically reduced plasma cholesterol levels, whereas apoA-I gene did not substantially change the mouse lipid profile. For each treatment a significant reduction of atherosclerosis progression was observed.