Research advances may target varicose vein therapies

National report - A single intracellular molecule, activator protein-1 (AP-1), appears to initiate the signaling cascade for vascular remodeling that results in varicose veins. Assuming that these findings on the mechanisms of the disease in a mouse model translate into humans, they offer new targets for therapeutic intervention that go beyond current surgical options, a researcher says.

Thomas Korff, Ph.D., a vascular researcher at Heidelberg University, Tiffin, Ohio, approached the question from a physiological perspective and sought to determine “how pressure changes in veins may affect the vessel wall itself.”

Thomas Korff, M.D.

Prolonged standing changes the physical parameters affecting the vessel wall of the vein by increasing the hydrostatic pressure.

“As long as the valves in the veins are OK, it doesn’t matter; but if they are leaky, then the venous blood pressure rises, increases the wall stress and activates endothelial and smooth muscle cells in the vessel wall” - a sequence of events which triggers the disease process, he explains.

“We cannot treat the physical forces per se, but the change of the phenotype of those cells can be treated by inhibiting elements of the pathway that are activated in those cells. One of those is AP-1,” he says.

Lab simulation
Dr. Korff and the research team at the university's Institute of Physiology and Pathophysiology simulated varicosis by tying off a single vein in the ear of white mice to artificially increase pressure.

“We found that by simply increasing the pressure levels in veins we can initiate some changes in the vessel walls that are similar to what is seen in varicose veins,” he says.

Within four days, the vein had enlarged 2.5-fold, and there was an increase in smooth muscle cell proliferation, matrix metalloproteinase 2 (MMP-2), and gelatinase activity, all of which is characteristic of venous hypertension. Interestingly, researchers saw no evidence of inflammation in this early stage of tissue remodeling, Dr. Korff says.

AP-1 is a known factor in hypertension and also is known to regulate the expression of many genes associated with the processes that the researchers observed. Dr. Korff used a decoy oligonucleotide in a topical ointment to block the action of AP-1, locally inhibiting the transcription factor in the mice.

“The decoys are double-stranded fragments of DNA that are taken up by the cell, bind to transcription factors and inactivate them. They cannot be translocated to the nucleus and cannot become active,” he says.

The decoy worked as predicted, interrupting the AP-1 signal and associated gene expression.

“When you take out this critical part of the mechanism, either locally or systemically, then you can prevent the remodeling of the vessel walls, or at least slow that development.,” Dr. Korff says.

Cellular insights
“I thought the study was pretty cool, though that doesn’t sound very professional,” Danielle K. Moul, M.D., says. “It tells us the etiology of venous disease at the cellular level; how the cell responds to increased pressure and increased stress on the vein walls.

“I think it is the way that medicine is going to be headed,” she says. “We are going to be looking at much more targeted responses in treating disease at the origin rather than being reactionary.” Dr. Moul is a dermatologist with West Dermatology, Rancho Santa Margarita, Calif.

Dr. Moul makes the comparison with psoriasis where a deeper understanding of the immunologic mechanisms of the disease has led to the more targeted approach of interleukin (IL)-12/IL-23 inhibitors for treatment.

Translational medicine
Dr. Korff says he is hopeful that this finding in basic research may move toward clinical study quickly. He points out that the ointment containing the oligo decoy used in the animal study has already been used in clinical studies of dermatitis and psoriasis.

A topical product might have cosmetic use in treating surface varicose veins, but it appears to penetrate only about 1 mm into the skin. “Life-threatening varicose veins are the deep veins. I don’t think the local treatment can apply to those,” Dr. Korff says.

Dr. Korff says he sees varicose veins visible in the leg as the first visible manifestation of a systemic disease.

“Once a varicose vein has developed, the disease spreads over the connecting links, it does not stay local,” he says.

And that calls for a systemic intervention, he explains, ideally one that is orally available. He says he already has some candidates in mind.

“One side effect of some of the statin drugs used to treat high blood cholesterol - the scientific literature mentions atorvastatin and simvastatin - is that they inhibit the activity of AP-1,” Dr. Korff says.

Dr. Korff suggests a first and relatively inexpensive step, conducting a review of patient records “to see if the statin treatment affects the development of varicose veins,” and if the response varies between statins. If there is a positive signal, a randomized controlled trial with the most promising candidate could follow.

Local concern
Dr. Moul says she is inclined to view varicosity and its treatment as more of a localized than a systemic concern. “When looking at venous insufficiency, typically there is involvement of the superficial venous system rather than generalized systemic involvement of the deep and superficial venous system. When you look at most of our patients, the vast majority don’t have deep venous insufficiency, they just have superficial venous insufficiency,” she says. “Most of the superficial varicose veins, with the exception of the greater saphenous, which lies within the fascial plane within a centimeter or two below the skin.”

That suggest the potential use of a topical activator protein-1 inhibitor, which might minimize systemic exposure and potential risks, Dr. Moul says. She points out that the legs, the likely target for use, constitute 36 percent of the body’s surface area.

Can varicosity be reversed? Dr. Korff says he doubts that is possible.

“The structural changes in the vessel walls are really drastic - proliferation of muscle cells and enlargement of the vein. To reverse it would require stimulating apoptosis or necrosis of these muscle cells, which would be dangerous,” he says.

Dr. Korff says he believes the most successful course is likely to be early intervention to arrest or delay progression of varicosis.

Disclosures: No industry funds were used in the conduct of this basic research. Drs. Korff and Dr. Moul report no relevant financial interests.

For more information: Feldner A, Otto H, Rewerk S, Hecker M, Korff T. FASEB J. 2011;25(10):3613-3621.