Gene Transfer Into Normal and Atherosclerotic Human Blood Vessels

From the Departments of Pathology (M.D.R., C.W.W., D.G.), Internal Medicine (R.D.S., G.J.N., E.G.N.), and Physiology (E.G.N.), and Howard Hughes Medical Institute (G.J.N.), University of Michigan, Ann Arbor.

Correspondence to David Gordon, MD, Vascular and Cardiac Diseases, Parke-Davis Pharmaceutical Research Division, 2800 Plymouth Rd, Ann Arbor, MI 48105. E-mail gordond{at}aa.wl.com

Abstract—Gene transfer to blood vessels is a promising new approach to the treatment of the vascular diseases, but the feasibility of gene transfer to adult human vessels has not been explored. We introduced an adenovirus vector encoding a marker gene human placental alkaline phosphatase into normal and atherosclerotic human vessels in organ culture. In the normal vessels, recombinant gene was expressed preferentially in the endothelial cells (100%), intimal smooth muscle cells (1.3±0.4%, 1.4±1.0%, and 3.8±0.8% in the internal mammary arteries, saphenous veins, and normal coronary arteries, respectively), and various adventitial cells. Advanced, complicated atherosclerotic plaques demonstrated a similar efficiency of recombinant gene expression (3.1±0.5% and 3.8±0.3% of nonendothelial intimal cells in the coronary artery and carotid artery plaques, respectively). Of these intimal cells, macrophages and smooth muscle cells expressed a transgene, identifying them as targets for gene transfer. Areas of plaque rupture and thrombus are sites of predilection for expression of recombinant genes. Collagenase and elastase treatment increased the percentage of transgenic alkaline phosphatase–positive cells 7 times (P<0.001), suggesting that the pattern of gene expression was affected by the amount of surrounding extracellular matrix. These studies demonstrate the feasibility of gene transfer to human blood vessels. However, these studies also highlight important barriers to adenoviral gene delivery to the actual normal and atherosclerotic human vessels of clinical interest.

Key Words: gene transfer • smooth muscle cell • macrophage • arteriosclerosis • human

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