TY - JOUR
T1 - Tissue type plasminogen activator regulates myeloid-cell dependent neoangiogenesis during tissue regeneration
AU - Ohki, Makiko
AU - Ohki, Yuichi
AU - Ishihara, Makoto
AU - Nishida, Chiemi
AU - Tashiro, Yoshihiko
AU - Akiyama, Haruyo
AU - Komiyama, Hiromitsu
AU - Lund, Leif R
AU - Nitta, Atsumi
AU - Yamada, Kiyofumi
AU - Zhu, Zhenping
AU - Ogawa, Hideoki
AU - Yagita, Hideo
AU - Okumura, Ko
AU - Nakauchi, Hiromitsu
AU - Werb, Zena
AU - Heissig, Beate
AU - Hattori, Koichi
N1 - Keywords: Animals; Antigens, CD11b; Base Sequence; Bone Marrow Transplantation; DNA Primers; Female; Gene Expression; Ischemia; Male; Matrix Metalloproteinase 9; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Mutant Proteins; Myeloid Cells; Neovascularization, Physiologic; Plasminogen; Recombinant Proteins; Regeneration; Signal Transduction; Stem Cell Factor; Tissue Plasminogen Activator; Transplantation Chimera; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1
PY - 2010/5/27
Y1 - 2010/5/27
N2 - Ischemia of the heart, brain, and limbs is a leading cause of morbidity and mortality worldwide. Treatment with tissue type plasminogen activator (tPA) can dissolve blood clots and can ameliorate the clinical outcome in ischemic diseases. But the underlying mechanism by which tPA improves ischemic tissue regeneration is not well understood. Bone marrow (BM)-derived myeloid cells facilitate angiogenesis during tissue regeneration. Here, we report that a serpin-resistant form of tPA by activating the extracellular proteases matrix metalloproteinase-9 and plasmin expands the myeloid cell pool and mobilizes CD45+ CD11b+ proangiogenic, myeloid cells, a process dependent on vascular endothelial growth factor-A (VEGF-A) and Kit ligand signaling. tPAimproves the incorporation of CD11b+ cells into ischemic tissues and increases expression of neoangiogenesis-related genes, including VEGF-A. Remarkably, transplantation of BM-derived tPA-mobilized CD11b+ cells and VEGFR-1+ cells, but not carriermobilized cells or CD11b- cells, accelerates neovascularization and ischemic tissue regeneration. Inhibition of VEGF signaling suppresses tPA-induced neovascularization in a model of hind limb ischemia. Thus, tPA mobilizes CD11b+ cells from the BM and increases systemic and local (cellular) VEGF-A, which can locally promote angiogenesis during ischemic recovery. tPA might be useful to induce therapeutic revascularization in the growing field of regenerative medicine.
AB - Ischemia of the heart, brain, and limbs is a leading cause of morbidity and mortality worldwide. Treatment with tissue type plasminogen activator (tPA) can dissolve blood clots and can ameliorate the clinical outcome in ischemic diseases. But the underlying mechanism by which tPA improves ischemic tissue regeneration is not well understood. Bone marrow (BM)-derived myeloid cells facilitate angiogenesis during tissue regeneration. Here, we report that a serpin-resistant form of tPA by activating the extracellular proteases matrix metalloproteinase-9 and plasmin expands the myeloid cell pool and mobilizes CD45+ CD11b+ proangiogenic, myeloid cells, a process dependent on vascular endothelial growth factor-A (VEGF-A) and Kit ligand signaling. tPAimproves the incorporation of CD11b+ cells into ischemic tissues and increases expression of neoangiogenesis-related genes, including VEGF-A. Remarkably, transplantation of BM-derived tPA-mobilized CD11b+ cells and VEGFR-1+ cells, but not carriermobilized cells or CD11b- cells, accelerates neovascularization and ischemic tissue regeneration. Inhibition of VEGF signaling suppresses tPA-induced neovascularization in a model of hind limb ischemia. Thus, tPA mobilizes CD11b+ cells from the BM and increases systemic and local (cellular) VEGF-A, which can locally promote angiogenesis during ischemic recovery. tPA might be useful to induce therapeutic revascularization in the growing field of regenerative medicine.
U2 - 10.1182/blood-2009-08-236851
DO - 10.1182/blood-2009-08-236851
M3 - Journal article
C2 - 20110420
SN - 0006-4971
VL - 115
SP - 4302
EP - 4312
JO - Blood
JF - Blood
IS - 21
ER -