Abstract 14292: KLF5 Contributes to in vivo Thrombus Formation and Cytokine-induced and Tumor-associated Angiogenesis
Thrombosis plays a central role in the pathogenesis of various cardiovascular and cerebral diseases. Moreover, platelets are known as essential elements not only of hemostasis and thrombosis but also of atherosclerosis, inflammation, and angiogenesis. Therefore, the precise mechanism that regulates platelet function remains one of the most extensively studied research areas, aiming to possible therapeutic interventions. Here we show a novel Krüppel-like factor 5 (KLF5)-dependent regulation of in vivo thrombus formation and angiogenesis using platelet lineage-specific Klf5-knockout (Klf5fl/fl; Pf4-Cre) mice. First, we revealed that in vivo thrombus formation triggered by laser irradiation was significantly impaired in these mice. These mice also exhibited longer tail bleeding time and more frequent re-bleeding, indicating thrombus instability. Next, we investigated platelet-specific adhesion molecules on washed platelets isolated from these mice. Klf5fl/fl; Pf4-Cre platelets had a heterogeneous expression pattern of surface glycoproteins, and some platelets showed impaired expression of all 4 subunits of the von Willebrand Factor receptor, glycoprotein (GP) Ib-IX-V, as well as the collagen receptor GPVI. Surface expression levels of these glycoproteins were also impaired in Klf5fl/fl; Pf4-Cre megakaryocytes in bone marrow. These were at least partly due to deregulated membrane trafficking and enhanced shedding, or extracellular proteolysis, of these adhesion molecules. With these results, we speculated that these mice might have diminished angiogenesis activities. As expected, two in vivo angiogenesis assays clearly demonstrated that Klf5fl/fl; Pf4-Cre mice had significantly attenuated cytokine-induced and tumor-associated angiogenesis, which led to reduced growth of implanted tumors. Our findings are consistent with the notion that functional defects of platelets alone are sufficient to impair in vivo angiogenesis. In conclusion, we have shown KLF5 critically contributes to in vivo thrombus formation and angiogenesis. Our findings advance our understanding of the mechanisms of platelet pathophysiology in a wide range of diseases, including not only cardiovascular but also malignant diseases.
- © 2013 by American Heart Association, Inc.