Balloon angioplasty unblocks a clot-clogged artery the way a roto-rooter clears out a filth-filled sewer.
To break up and remove atherosclerotic stenosis _ occluding ornarrowing of a coronary artery _ the cardiac surgeon threads aslender balloon into the occluded blood vessel and inflates it througha catheter.
With this log jam out of the way, more blood courses into theoxygen-starved heart, to the relief of patient and surgeon alike.
Their relief is temporary.
The endothelial cells that line the arterial lumen see that clot-destroying, life-prolonging surgical ploy as an insult to their cellularintegrity. During its brief sojourn in the artery, that inflated balloonrubs against the lumenal wall and bruises those delicate cells. Thisinjury sets off a 911-like alarm in the endothelium, which summonsits swat team to repair the lesion _ with a new clot.
The word for this knee-jerk overreaction is restenosis, "which causesdevastating clinical problems," in the words of molecular biologistand endotheliologist Tucker Collins. "In the context of restenosis,"Collins told BioWorld Today, "one has to view the cause of injury asthe cardiologist's balloon catheter." Viewed from the perspective ofan endothelial cell, he continued, "this vascular injury is the sledge-hammer-like application of denuding injury."
In 40 to 60 percent of these angioplastic interventions, restenosisoccurs. This then becomes the target of a return engagement with theballoon.
That endothelial damage, Collins explained, "leads to recruitmentand proliferation of smooth muscle cells from the muscular layers ofthe artery to its interior sections, or lumen." Those cells are the maincause and constituent of restenosis.
Chronic atherosclerotic build-up, driven by slow-acting hypertension,smoking, lipid profiles and high blood pressure, may take years anddecades to build up in coronary arteries. Restenosis takes typicallysix months to two years, Collins pointed out.
When angioplasty and all else fail, he went on, heart transplant is theultimate therapy. But even an organ graft doesn't defeat restenosis."The long-term survival of a cardiac allograft transplantation," hesaid, "is limited by the formation of these occlusive lesions in thetransplant coronary arteries."
Collins teaches pathology at Harvard Medical School, and researchesthe endothelial response to wounding at Brigham & Women'sHospital. He is senior author of a report in the current Science, datedMarch 8, 1996, titled: "Egr-1-induced endothelial gene expression: acommon theme in vascular injury."
Collins' point of departure is a series of growth factors induced bythe insulted endothelial cells into the vasculature after acutemechanical injury. Prime among these is platelet-derived growthfactor (PDGF), expressed by genes in the cells.
When this takes place, he recalled, "we were struck by the fact thatthere was a dramatic up-regulation in an immediate early growthfactor regulatory gene known as Egr-1. But it wasn't clear to usexactly what genes Egr-1 actually regulated.
"Egr-1 expression," in the balloon-damaged aortas of rats, their paperreports, "was markedly induced exclusively at the endothelial woundedge within 30 minutes of partial denudation."
They found that it sat between the A and B chains of PDGF.Experiments described in the Science paper, Collins said, "suggestedthat injury-induced Egr-1 was driving the expression of both chains.Not only these chains," he added, "but, as other investigators found, aseries of relevant genes have binding sites for Egr-1."
They galvanize endothelial cells into activating smooth muscle cellsto multiply, and attract them to the scene of the wound. This "leads toformation of the clotting complex that eventuates in restenosis."
On the way to this outcome, the co-authors found that the Egr-1 gene,when aroused, actually nudges another gene, Sp1 out of its way onthe PDGF chains. It expresses a ubiquitous transcription factor, Sp1,which acts _ while it has the chance _ to inhibit inadvertentendothelial response in the absence of injury. n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.