Regulation of neovascularization by human neutrophil peptides (α‐defensins): a link between inflammation and angiogenesis

Abstract

Angiogenesis, the growth of new blood vessels, is a complex biological process that is orchestrated by several growth factors and components of the extracellular matrix, including fibronectin (FN) and its receptor the integrin alpha5beta1. Angiogenesis is a critical part of inflammation and wound repair, but the mechanism by which vascular proliferation and migration is regulated by inflammatory cells is not completely understood. We have previously shown that human neutrophil peptides (HNPs), also known as alpha-defensins, which are secreted in high concentrations when neutrophils are activated, bind specifically to FN in the extracellular matrix and inhibit plasminogen activation. Therefore, we asked whether HNPs act as a link between inflammation and angiogenesis. Alpha5beta1-mediated endothelial cell adhesion and migration to FN, both under control conditions and under stimulation by vascular endothelial growth factor (VEGF), were inhibited specifically and in a dose-dependent manner by HNPs, whereas endothelial cell adhesion and migration to other components of the extracellular matrix, such as vitronectin, collagen, or fibrinogen/fibrin were not. Consistent with this finding, HNPs bound to and promoted the binding of fibronectin to alpha5beta1 integrin in arginine-glycine-aspartic acid (RGD)-independent manner. HNPs also completely inhibited VEGF-induced proliferation and induced apoptosis of endothelial cells in a dose-dependent manner. Moreover, HNPs inhibited capillary tube formation in three-dimensional fibrin-matrices as well as neovascularization in vivo in the chicken chorioallantoic membrane assay. Taken together, these data indicate that HNPs can regulate angiogenesis by affecting endothelial cell adhesion and migration in an FN-dependent manner as well as endothelial cell proliferation. These findings provide new insight into the role of inflammatory cells in angiogenesis and might provide a platform for developing a novel class of anti-angiogenesis drugs.

Proteomic analysis reveals successive aberrations in protein expression from healthy mucosa to invasive head and neck cancer

“…It is likely that the defensins support angiogenesis already during premalignancy, in agreement with similar findings in experimental premalignancy (Smith-McCune, 1997). Thus, the defensins represent an important link between inflammation, angiogenesis and cancer (Chavakis et al, 2004). Our findings on the calgranulins A and B further underline this concept: in contrast to the defensins, the calgranulins are expressed in both epithelia and neutrophils but likely with different activities.…”

Angiogenesis in Platelet Endothelial Cell Adhesion Molecule-1-Null Mice

“…[43][44][45][46][47][48] The absence of PECAM-1 on these bone marrow-derived cells, in addition to the loss of PECAM-1 on ECs, could contribute to the altered angiogenic phenotype of the PECAM-1-deficient mice. The inability of wild-type PE-CAM-1-expressing leukocytes and/or bone marrow-derived endothelial progenitor cells to restore the wild-type phenotype in the PECAM-1-null animals (WT BM -KO EC ) provides strong evidence for the endothelial involvement of PECAM-1 during in vivo angiogenesis (Figure 4).…”

“…2 Recruited leukocytes, tissue macrophages, and circulating bone marrow-derived progenitor endothelial cells have been identified as cellular participants during in vivo angiogenesis and thus, as PECAM-1 expressing cells, they may also contribute to the participation of PECAM-1 in this process. [43][44][45][46][47][48] To identify the possible involvement of PECAM-1 expressed on leukocytes, macrophages, and/or circulating endothelial progenitor cells in vessel formation, bone marrow chimeric animals were generated to selectively propagate bone marrow-derived wild-type vascular cells against a background of PECAM-1-deficient endothelium. This approach was used successfully to distinguish the importance of endothelial versus platelet PECAM-1 in hemostasis.…”

Intratumoral expression of mature human neutrophil peptide-1 potentiates the therapeutic effect of doxorubicin in a mouse 4T1 breast cancer model

“…We also noted that the intratumoral expression of HNP1 mediated specific angiogenesis inhibition in vivo (17,18). In addition, HNP1 can cause VEGF-dependent endothelial cell proliferation inhibition by forming a ternary complex with fibronectin and α 5 β 1 integrin (19). In addition, there are reports that inhibition of VEGF-mediated angiogenesis can improve chemotherapy efficacy via inducing tumor microvessel normalization (20,21).…”