Tissue type plasminogen activator regulates myeloid-cell dependent neoangiogenesis during tissue regeneration.

Abstract:

: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. tPA improves 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 carrier-mobilized 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.

journal_name

Blood

journal_title

Blood

authors

Ohki M,Ohki Y,Ishihara M,Nishida C,Tashiro Y,Akiyama H,Komiyama H,Lund LR,Nitta A,Yamada K,Zhu Z,Ogawa H,Yagita H,Okumura K,Nakauchi H,Werb Z,Heissig B,Hattori K

doi

10.1182/blood-2009-08-236851

subject

Has Abstract

pub_date

2010-05-27 00:00:00

pages

4302-12

issue

21

eissn

0006-4971

issn

1528-0020

pii

blood-2009-08-236851

journal_volume

115

pub_type

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