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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:2310.)
© 2007 American Heart Association, Inc.

Vascular Biology

Natural Killer Cells and CD4⁺ T-Cells Modulate Collateral Artery Development

V. van Weel; R.E.M. Toes; L. Seghers; M.M.L. Deckers; M.R. de Vries; P.H. Eilers; J. Sipkens; A. Schepers; D. Eefting; V.W.M. van Hinsbergh; J.H. van Bockel; P.H.A. Quax

From the Gaubius Laboratory (V.v.W., L.S., M.M.L.D., M.R.d.V., J.S., A.S., D.E., P.H.A.Q.), TNO Quality of Life, Leiden, the Netherlands; and the Departments Surgery (V.v.W., A.S., D.E., J.H.v.B., P.H.A.Q.), Rheumatology (R.E.M.T.), and Medical Statistics (P.H.E.), Leiden University Medical Center (LUMC), Leiden, the Netherlands, and Laboratory for Physiology, ICAR-VU, VU University Medical Center, Amsterdam, the Netherlands (L.S., V.W.M.v.H.).

Correspondence to Dr P.H.A. Quax, TNO-QOL, P.O. Box 2215, 2301CE Leiden, the Netherlands. E-mail paul.quax{at}tno.nl

Objective— The immune system is thought to play a crucial role in regulating collateral circulation (arteriogenesis), a vital compensatory mechanism in patients with arterial obstructive disease. Here, we studied the role of lymphocytes in a murine model of hindlimb ischemia.

Methods and Results— Lymphocytes, detected with markers for NK1.1, CD3, and CD4, invaded the collateral vessel wall. Arteriogenesis was impaired in C57BL/6 mice depleted for Natural Killer (NK)-cells by anti-NK1.1 antibodies and in NK-cell–deficient transgenic mice. Arteriogenesis was, however, unaffected in J281-knockout mice that lack NK1.1⁺ Natural Killer T (NKT)-cells, indicating that NK-cells, rather than NKT-cells, are involved in arteriogenesis. Furthermore, arteriogenesis was impaired in C57BL/6 mice depleted for CD4⁺ T-lymphocytes by anti-CD4 antibodies, and in major histocompatibility complex (MHC)-class-II–deficient mice that more selectively lack mature peripheral CD4⁺ T-lymphocytes. This impairment was even more profound in anti-NK1.1-treated MHC-class-II–deficient mice that lack both NK- and CD4⁺ T-lymphocytes. Finally, collateral growth was severely reduced in BALB/c as compared with C57BL/6 mice, 2 strains with different bias in immune responsiveness.

Conclusions— These data show that both NK-cells and CD4⁺ T-cells modulate arteriogenesis. Promoting lymphocyte activation may represent a promising method to treat ischemic disease.

The immune system is thought to play a crucial role in regulating collateral circulation (arteriogenesis). Here, we show that both natural killer cells and CD4⁺ T-cells modulate arteriogenesis. Promoting lymphocyte activation may represent a promising method to treat ischemic disease.

Key Words: peripheral vascular disease • angiogenesis • animal models of human disease

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