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Published 9 October 2006. doi:10.1083/jcb.200603176
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 175, Number 1, 179-191
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Article

Coregulation of vascular tube stabilization by endothelial cell TIMP-2 and pericyte TIMP-3



W. Brian Saunders1, Brenda L. Bohnsack4, Jennifer B. Faske1, Nicholas J. Anthis1, Kayla J. Bayless1, Karen K. Hirschi4, and George E. Davis1,2,3

1 Department of Pathology and Laboratory Medicine, Texas A&M University System Health Science Center, College Station, TX 77843
2 Department of Medical Pharmacology and Physiology and 3 Department of Pathology and Anatomical Sciences, School of Medicine, Christopher S. Bond Life Sciences Center and Dalton Cardiovascular Research Center, University of Missouri-Columbia, Columbia, MO 65212
4 Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030

Correspondence to George E. Davis: davisgeo{at}health.missouri.edu

The endothelial cell (EC)–derived tissue inhibitor of metalloproteinase-2 (TIMP-2) and pericyte-derived TIMP-3 are shown to coregulate human capillary tube stabilization following EC–pericyte interactions through a combined ability to block EC tube morphogenesis and regression in three-dimensional collagen matrices. EC–pericyte interactions strongly induce TIMP-3 expression by pericytes, whereas ECs produce TIMP-2 in EC–pericyte cocultures. Using small interfering RNA technology, the suppression of EC TIMP-2 and pericyte TIMP-3 expression leads to capillary tube regression in these cocultures in a matrix metalloproteinase-1 (MMP-1)–, MMP-10–, and ADAM-15 (a disintegrin and metalloproteinase-15)–dependent manner. Furthermore, we show that EC tube morphogenesis (lumen formation and invasion) is primarily controlled by the TIMP-2 and -3 target membrane type (MT) 1 MMP. Additional targets of these inhibitors include MT2-MMP and ADAM-15, which also regulate EC invasion. Mutagenesis experiments reveal that TIMP-3 requires its proteinase inhibitory function to induce tube stabilization. Overall, these data reveal a novel role for both TIMP-2 and -3 in the pericyte-induced stabilization of newly formed vascular networks that are predisposed to undergo regression and reveal specific molecular targets of the inhibitors regulating these events.

Abbreviations used in this paper: ADAM, a disintegrin and metalloproteinase; BRP, bovine retinal pericyte; CASMC, coronary artery smooth muscle cell; DN, downstream primer; EC, endothelial cell; HUVEC, human umbilical vein EC; MMP, matrix metalloproteinase; MT, membrane type; Plg, plasminogen; S1P, sphingosine-1 phosphate; SDF-1{alpha}, stromal-derived factor-1{alpha}; TIMP, tissue inhibitor of metalloproteinase; UP, upstream primer; VE, vascular endothelial; VEGFR-2, VEGF receptor-2.


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