RESUMO
CD34+ bone marrow-derived progenitor cells contribute to tissue repair by differentiating into endothelial cells, vascular smooth muscle cells, hematopoietic cells, and possibly other cell types. However, the mechanisms by which circulating progenitor cells home to remodeling tissues remain unclear. Here we show that integrin alpha4beta1 (VLA-4) promotes the homing of circulating progenitor cells to the alpha4beta1 ligands VCAM and cellular fibronectin, which are expressed on actively remodeling neovasculature. Progenitor cells, which express integrin alpha4beta1, homed to sites of active tumor neovascularization but not to normal nonimmune tissues. Antagonists of integrin alpha4beta1, but not other integrins, blocked the adhesion of these cells to endothelia in vitro and in vivo as well as their homing to neovasculature and outgrowth into differentiated cell types. These studies describe an adhesion event that facilitates the homing of progenitor cells to the neovasculature.
Assuntos
Células da Medula Óssea/fisiologia , Movimento Celular/fisiologia , Células-Tronco Hematopoéticas/fisiologia , Neovascularização Fisiológica , Animais , Antígenos CD34/metabolismo , Células da Medula Óssea/citologia , Antígenos CD18/fisiologia , Adesão Celular/fisiologia , Endotélio Vascular/citologia , Endotélio Vascular/fisiologia , Células-Tronco Hematopoéticas/citologia , Humanos , Integrina alfa4beta1/genética , Integrina alfa4beta1/metabolismo , CamundongosRESUMO
Neovascularization depends on vascular cell proliferation and on the stabilization of vessels by association of vascular smooth muscle-like pericytes with ECs. Here we show that integrin alpha4beta1 (VLA-4) and VCAM-1 promote close intercellular adhesion between ECs and pericytes and that this interaction is required for blood vessel formation. Integrin alpha4beta1 is expressed by proliferating but not quiescent ECs, while its ligand VCAM-1 is expressed by proliferating but not quiescent mural cells. Antagonists of this integrin-ligand pair block the adhesion of mural cells to proliferating endothelia in vitro and in vivo, thereby inducing apoptosis of ECs and pericytes and inhibiting neovascularization. These studies indicate that integrin alpha4beta1 and VCAM-1 facilitate a critical cell-cell adhesion event required for survival of endothelial and mural cells during vascularization.
Assuntos
Vasos Sanguíneos/metabolismo , Endotélio Vascular/metabolismo , Integrina alfa4beta1/biossíntese , Neoplasias/irrigação sanguínea , Neovascularização Patológica/metabolismo , Molécula 1 de Adesão de Célula Vascular/biossíntese , Animais , Vasos Sanguíneos/patologia , Adesão Celular , Proliferação de Células , Sobrevivência Celular , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Endotélio Vascular/patologia , Feminino , Humanos , Integrina alfa4beta1/antagonistas & inibidores , Camundongos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Neoplasias/patologia , Neovascularização Patológica/patologia , Pericitos/metabolismo , Pericitos/patologiaRESUMO
Monocytes and macrophages extensively colonize solid tumors, where they are thought to promote tumor angiogenesis. Here, we show that integrin alpha4beta1 (VLA4) promotes the invasion of tumors by myeloid cells and subsequent neovascularization. Antagonists of integrin alpha4beta1, but not of other integrins, blocked the adhesion of monocytes to endothelium in vitro and in vivo as well as their extravasation into tumor tissue. These antagonists prevented monocyte stimulation of angiogenesis in vivo, macrophage colonization of tumors, and tumor angiogenesis. These studies indicate the usefulness of antagonists of integrin alpha4beta1 in suppressing macrophage colonization of tumors and subsequent tumor angiogenesis. These studies further indicate that suppression of myeloid cell homing to tumors could be a useful supplementary approach to suppress tumor angiogenesis and growth.
Assuntos
Carcinoma Pulmonar de Lewis/irrigação sanguínea , Neoplasias do Colo/irrigação sanguínea , Integrina alfa4beta1/fisiologia , Leucócitos Mononucleares/fisiologia , Animais , Carcinoma Pulmonar de Lewis/patologia , Adesão Celular/fisiologia , Neoplasias do Colo/patologia , Células Endoteliais/patologia , Células HT29 , Humanos , Leucócitos Mononucleares/citologia , Linfangiogênese , Macrófagos/citologia , Macrófagos/fisiologia , Camundongos , Camundongos Nus , Células Mieloides/patologia , Neovascularização Patológica/patologiaRESUMO
Integrins are cell adhesion molecules that play an important role in the regulation of angiogenesis. In this overview, the vascular integrins and their mechanisms of action are outlined. Integrins have been evaluated in preclinical and clinical studies for the treatment of cancer and as diagnostic markers of angiogenesis. Furthermore, integrins are the basis for targeted therapy for solid tumors and novel imaging techniques to assess the angiogenic response of tumors.