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Src and phosphatidylinositol 3-kinase mediate soluble E-selectin-induced angiogenesis
Pawan Kumar1, Mohammad A Amin, Lisa A Harlow
1Veterans Administration, Lakeside Division, Chicago Health Care System, Chicago, IL, USA.
Blood
|January 11, 2003
Summary
Soluble E-selectin (sE-selectin) drives angiogenesis by activating the Src-phosphatidylinositol 3-kinase (PI3K) pathway in endothelial cells. This mechanism is crucial for blood vessel formation in conditions like tumor growth and arthritis.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Angiogenesis is vital in pathological processes such as tumor growth and rheumatoid arthritis.
- Soluble E-selectin (sE-selectin) has been identified as a significant mediator of angiogenesis.
- The precise molecular mechanisms underlying sE-selectin's role in angiogenesis remain largely unelucidated.
Purpose of the Study:
- To investigate the signaling pathways through which sE-selectin mediates angiogenesis.
- To determine the role of Src, phosphatidylinositol 3-kinase (PI3K), and extracellular signal-related kinase 1/2 (ERK1/2) in sE-selectin-induced endothelial cell behavior.
- To elucidate the mechanism of sE-selectin-driven angiogenesis in human dermal microvascular endothelial cells (HMVECs).
Main Methods:
- Utilized in vitro assays, including HMVEC chemotaxis and Matrigel tube formation assays.
- Employed specific inhibitors (PP2 for Src, LY294002 for PI3K, PD98059 for MAPK/ERK1/2) and genetic manipulation (antisense oligonucleotides, dominant-negative mutants).
- Assessed protein phosphorylation (Src, ERK1/2, PI3K, Akt) and in vivo Matrigel-plug assays to evaluate blood vessel formation.
Main Results:
- sE-selectin potently mediated HMVEC chemotaxis and tube formation, with a 2.2-fold increase observed in vitro.
- Inhibition of Src and PI3K pathways significantly blocked sE-selectin-induced HMVEC tube formation and in vivo blood vessel formation.
- While sE-selectin activated ERK1/2, this pathway was not essential for angiogenesis, and Src kinase appeared to activate both PI3K and ERK1/2 pathways.
Conclusions:
- sE-selectin-induced angiogenesis is predominantly mediated by the Src-PI3K signaling pathway.
- The Src-PI3K axis is critical for endothelial cell migration, tube formation, and blood vessel development stimulated by sE-selectin.
- Targeting the Src-PI3K pathway may offer therapeutic strategies for angiogenesis-related diseases.