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Updated: Apr 23, 2026
Author Spotlight: Development of a Method for Identifying Small Molecular Antagonists of β2 Integrin Activation
Published on: February 2, 2024
Dual role of the leukocyte integrin αMβ2 in angiogenesis
Dmitry A Soloviev1, Stanley L Hazen2, Dorota Szpak1
1Department of Molecular Cardiology, Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Learner Research Institute, Cleveland Clinic, Cleveland, OH 44195;
Abstract:
Polymorphonuclear neutrophils (PMNs) and macrophages are crucial contributors to neovascularization, serving as a source of chemokines, growth factors, and proteases. α(M)β(2)(CD11b/CD18) and α(L)β(2)(CD11a/CD18) are expressed prominently and have been implicated in various responses of these cell types. Thus, we investigated the role of these β2 integrins in angiogenesis. Angiogenesis was analyzed in wild-type (WT), α(M)-knockout (α(M)(-/-)), and α(L)-deficient (α(L)(-/-)) mice using B16F10 melanoma, RM1 prostate cancer, and Matrigel implants. In all models, vascular area was decreased by 50-70% in α(M)(-/-) mice, resulting in stunted tumor growth as compared with WT mice. In contrast, α(L) deficiency did not impair angiogenesis and tumor growth. The neovessels in α(M)(-/-) mice were leaky and immature because they lacked smooth muscle cell and pericytes. Defective angiogenesis in the α(M)(-/-) mice was associated with attenuated PMN and macrophage recruitment into tumors. In contrast to WT or the α(L)(-/-) leukocytes, the α(M)(-/-) myeloid cells showed impaired plasmin (Plm)-dependent extracellular matrix invasion, resulting from 50-75% decrease in plasminogen (Plg) binding and pericellular Plm activity. Surface plasmon resonance verified direct interaction of the α(M)I-domain, the major ligand binding site in the β(2) integrins, with Plg. However, the α(L)I-domain failed to bind Plg. In addition, endothelial cells failed to form tubes in the presence of conditioned medium collected from TNF-α-stimulated PMNs derived from the α(M)(-/-) mice because of severely impaired degranulation and secretion of VEGF. Thus, α(M)β(2) plays a dual role in angiogenesis, supporting not only Plm-dependent recruitment of myeloid cells to angiogenic niches, but also secretion of VEGF by these cells.
Insights
The α(M)β(2) integrin is crucial for blood vessel formation (angiogenesis) by supporting immune cell recruitment and vascular endothelial growth factor (VEGF) secretion. Its absence stunts tumor growth and impairs neovascularization.
Area of Science:
- Immunology
- Cell Biology
- Oncology
Background:
- Polymorphonuclear neutrophils (PMNs) and macrophages are vital for neovascularization, producing essential factors for blood vessel growth.
- Beta-2 (β2) integrins, specifically α(M)β(2) and α(L)β(2), are expressed on these myeloid cells and play roles in their functions.
- The specific roles of α(M)β(2) and α(L)β(2) integrins in angiogenesis remain to be fully elucidated.
Purpose of the Study:
- To investigate the role of β2 integrins, particularly α(M)β(2) and α(L)β(2), in the process of angiogenesis.
- To determine the impact of these integrins on tumor growth and neovascularization in vivo.
- To elucidate the underlying molecular mechanisms by which α(M)β(2) influences angiogenesis.
Main Methods:
- Angiogenesis and tumor growth were analyzed in wild-type (WT), α(M)-knockout (α(M)(-/-)), and α(L)-deficient (α(L)(-/-)) mice using B16F10 melanoma, RM1 prostate cancer, and Matrigel implants.
- Immune cell recruitment, extracellular matrix invasion, plasminogen (Plg) binding, and plasmin (Plm) activity were assessed in myeloid cells from these mouse models.
- Direct interaction between integrin I-domains and Plg was verified using surface plasmon resonance.
- Endothelial cell tube formation assays were performed using conditioned media from stimulated PMNs.
Main Results:
- Vascular area and tumor growth were significantly reduced (50-70%) in α(M)(-/-) mice compared to WT mice, while α(L) deficiency had no significant effect.
- Neovessels in α(M)(-/-) mice were immature and leaky, with reduced smooth muscle cell and pericyte coverage.
- α(M)(-/-) myeloid cells exhibited impaired extracellular matrix invasion due to a 50-75% decrease in Plg binding and pericellular Plm activity.
- The α(M)I-domain directly bound Plg, whereas the α(L)I-domain did not.
- Endothelial cells failed to form tubes when cultured with conditioned medium from α(M)(-/-) PMNs, indicating impaired VEGF secretion.
Conclusions:
- The α(M)β(2) integrin plays a critical dual role in angiogenesis.
- It facilitates Plg-dependent recruitment of myeloid cells to angiogenic sites.
- It is also essential for the secretion of vascular endothelial growth factor (VEGF) by myeloid cells, thereby supporting neovascularization.
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