Coregulation of vascular tube stabilization by endothelial cell TIMP-2 and pericyte TIMP-3.
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.
Saunders
W Brian
WB
Department of Pathology and Laboratory Medicine, Texas A&M University System Health Science Center, College Station, TX 77843, USA.
Bohnsack
Brenda L
BL
Faske
Jennifer B
JB
Anthis
Nicholas J
NJ
Bayless
Kayla J
KJ
Hirschi
Karen K
KK
Davis
George E
GE
D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism; D020533:Angiogenesis Inhibitors / Q000235:genetics / Q000502:physiology*; D000818:Animals; D002196:Capillaries / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism; D002417:Cattle; D003094:Collagen; D004622:Embryo, Mammalian / Q000098:blood supply / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D053506:Matrix Metalloproteinase 10 / Q000378:metabolism; D053504:Matrix Metalloproteinases, Membrane-Associated / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008955:Models, Cardiovascular; D016296:Mutagenesis; D020286:Pericytes / Q000378:metabolism*; D034622:RNA Interference; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*
D020533:Angiogenesis Inhibitors; D008565:Membrane Proteins; C088390:TIMP3 protein, human; D019717:Tissue Inhibitor of Metalloproteinase-3; D019716:Tissue Inhibitor of Metalloproteinase-2; D003094:Collagen; D051722:ADAM Proteins; C098660:ADAM15 protein, human; D053504:Matrix Metalloproteinases, Membrane-Associated; D053506:Matrix Metalloproteinase 10; D020781:Matrix Metalloproteinase 1