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(Circulation Research. 2001;88:903.)
© 2001 American Heart Association, Inc.

Molecular Medicine

Infection of Endothelium With E1^-E4⁺, but Not E1^-E4^-, Adenovirus Gene Transfer Vectors Enhances Leukocyte Adhesion and Migration by Modulation of ICAM-1, VCAM-1, CD34, and Chemokine Expression

Shahin Rafii, Sergio Dias, Sarah Meeus, Koichi Hattori, Ramalingam Ramachandran, Fred Feuerback, Stefan Worgall, Neil R. Hackett, Ronald G. Crystal

From the Division of Hematology-Oncology (S.R., S.D., S.M., K.H.), Division of Pulmonary and Critical Care Medicine (R.R., F.F., S.W., R.G.C.), Belfer Gene Therapy Core Facility (N.R.H., R.G.C.), and Institute of Genetic Medicine (R.G.C.), Cornell University Medical College, New York, NY.

Correspondence to Shahin Rafii, MD, Cornell University Medical College, 1300 York Ave, Room D601, New York, NY 10021. E-mail srafii{at}mail.med.cornell.edu

Abstract—Intravascular introduction of replication-deficient adenoviral vectors (Advectors) provides an ideal model of delivery of transgenes for the treatment of various vascular abnormalities. On the basis of the knowledge that Advectors can induce inflammatory responses after intravascular administration, we speculated that cellular activation by Advector infection could directly modulate the endothelial cell (EC) adhesion molecule/chemokine expression repertoire. Infection of human umbilical vein ECs or bone marrow microvascular ECs with an E1^-E4⁺ Advector resulted in the upregulation of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and CD34, but not E-selectin, P-selectin, CD36, CD13, CD44, HLA-DR or PECAM. Upregulation of ICAM-1, VCAM-1, and CD34 was apparent 12 hours after infection and persisted for weeks after infection. Selective induction of adhesion molecules was mediated by the presence of the E4 gene in the Advector, because infection of ECs with an E1^-E4^- Advector had no effect on adhesion molecule expression. ECs infected with E1^-E4⁺ Advector, but not those infected with E1^-E4^- Advector, supported the adhesion of leukocytes. Monoclonal antibodies to ICAM-1 and VCAM-1 inhibited adhesion of leukocytes to E1^-E4⁺-infected ECs. Infection of the ECs with E1^-E4⁺ Advector, but not E1^-E4^- Advector, resulted in downregulation of expression of chemocytokines, including interleukin-8, MCP-1, RANTES, and GM-CSF. Nonetheless, a large number of leukocytes migrated through ECs infected with E1^-E4⁺, but not those infected with E1^-E4^l-, in response to exogenous chemokines. These results demonstrate that infection of ECs with E1^-E4⁺ Advectors, but not E1^-E4^- Advectors, may directly augment inflammatory responses by upregulating expression of adhesion molecules and enhancing migration through Advector-infected ECs and suggest that E1^-E4^- Advectors may be a better choice for gene-transfer strategies directed to the ECs.

Key Words: endothelial activation • adhesion molecules • E4⁺ adenoviral vectors • leukocyte adhesion

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