Inflammation in wound repair: molecular and cellular mechanisms.

Blood vessels and lymphatic vessels form extensive networks that are essential for the transport of fluids, gases, macromolecules and cells within the large and complex bodies of vertebrates. Both of these vascular structures are lined with endothelial cells that integrate functionally into different organs, acquire tissue-specific specialization and retain plasticity; thereby, they permit growth during tissue repair or in disease settings. The angiogenic growth of blood vessels and lymphatic vessels coordinates several biological processes such as cell proliferation, guided migration, differentiation and cell-cell communication.

Molecular regulation of angiogenesis and lymphangiogenesis.

Inflammation is usually analysed from the perspective of tissue-infiltrating leukocytes. Microvascular endothelial cells at a site of inflammation are both active participants in and regulators of inflammatory processes. The properties of endothelial cells change during the transition from acute to chronic inflammation and during the transition from innate to adaptive immunity. Mediators that act on endothelial cells also act on leukocytes and vice versa. Consequently, many anti-inflammatory therapies influence the behaviour of endothelial cells and vascular therapeutics influence inflammation. This Review describes the functions performed by endothelial cells at each stage of the inflammatory process, emphasizing the principal mediators and signalling pathways involved and the therapeutic implications.

Evolving functions of endothelial cells in inflammation

Angiogenesis, the growth of blood vessels, is a fundamental biological process that controls embryonic development and is also involved in numerous life-threatening human diseases. Much work in the field of angiogenesis research has centred on the vascular endothelial growth factor (VEGF)-VEGF receptor system. The Tie receptors and their angiopoietin (Ang) ligands have been identified as the second vascular tissue-specific receptor Tyr kinase system. Ang-Tie signalling is essential during embryonic vessel assembly and maturation, and functions as a key regulator of adult vascular homeostasis. The structural characteristics and the spatio-temporal regulation of the expression of receptors and ligands provide unique insights into the functions of this vascular signalling system.

Control of vascular morphogenesis and homeostasis through the angiopoietin–Tie system

Mural cells are essential components of blood vessels and are necessary for normal development, homeostasis, and organ function. Alterations in mural cell density or the stable attachment of mural cells to the endothelium is associated with several human diseases such as diabetic retinopathy, venous malformation, and hereditary stroke. In addition mural cells are implicated in regulating tumor growth and have thus been suggested as potential antiangiogenic targets in tumor therapy. In recent years our knowledge of mural cell function and endothelial-mural cell signaling has increased dramatically, and we now begin to understand the mechanistic basis of the key signaling pathways involved. This is mainly thanks to sophisticated in vivo experiments using a broad repertoire of genetic technologies. In this review, we summarize the five currently best understood signaling pathways implicated in mural cell biology. We discuss PDGFB/PDGFRbeta- dependent pericyte recruitment, as well as the role of angiopoietins and Tie receptors in vascular maturation. In addition, we highlight the effects of sphingosine-1-phosphate signaling on adherens junction assembly and vascular stability, as well as the role of TGF-beta-signaling in mural cell differentiation. We further reflect recent data suggesting an important function for Notch3 signaling in mural cell maturation.

Endothelial-Mural Cell Signaling in Vascular Development and Angiogenesis

The angiopoietins Ang-1 and Ang-2 have been identified as ligands of the receptor tyrosine kinase Tie-2 (refs. 1,2). Paracrine Ang-1-mediated activation of Tie-2 acts as a regulator of vessel maturation and vascular quiescence. In turn, the antagonistic ligand Ang-2 acts by an autocrine mechanism and is stored in endothelial Weibel-Palade bodies from where it can be rapidly released upon stimulation. The rapid release of Ang-2 implies functions of the angiopoietin-Tie system beyond its established role during vascular morphogenesis as a regulator of rapid vascular responses. Here we show that mice deficient in Ang-2 (encoded by the gene Angpt2) cannot elicit an inflammatory response in thioglycollate-induced or Staphylococcus aureus-induced peritonitis, or in the dorsal skinfold chamber model. Recombinant Ang-2 restores the inflammation defect in Angpt2(-/-) mice. Intravital microscopy showed normal TNF-alpha-induced leukocyte rolling in the vasculature of Angpt2(-/-)mice, but rolling cells did not firmly adhere to activated endothelium. Cellular experiments showed that Ang-2 promotes adhesion by sensitizing endothelial cells toward TNF-alpha and modulating TNF-alpha-induced expression of endothelial cell adhesion molecules. Together, these findings identify Ang-2 as an autocrine regulator of endothelial cell inflammatory responses. Ang-2 thereby acts as a switch of vascular responsiveness exerting a permissive role for the activities of proinflammatory cytokines.

Angiopoietin-2 sensitizes endothelial cells to TNF-alpha and has a crucial role in the induction of inflammation.

The extracellular adherence protein (Eap) of Staphylococcus aureus inhibits wound healing by interfering with host defense and repair mechanisms

The extracellular adherence protein (Eap), a broad-spectrum adhesin secreted by Staphylococcus aureus, was previously shown to curb acute inflammatory responses, presumably through its binding to endothelial cell (EC) ICAM-1. Examining the effect of Eap on endothelial function in more detail, we here show that, in addition, Eap functions as a potent angiostatic agent. Concomitant treatment of EC with purified Eap resulted in the complete blockage of the mitogenic and sprouting responses elicited by vascular endothelial growth factor (VEGF)165 or basic fibroblast growth factor (bFGF). Moreover, the induction of tissue factor and decay-accelerating factor were repressed by Eap, as determined by qRT-polymerase chain reaction (qRT-PCR), with a corresponding reduction in Egr-1 protein up-regulation seen. This angiostatic activity was accompanied by a corresponding inhibition in ERK1/2 phosphorylation, while activation of p38 was not affected. Inhibition occurred downstream of tyrosine kinase receptor activatio...

The extracellular adherence protein from Staphylococcus aureus abrogates angiogenic responses of endothelial cells by blocking Ras activation.

Purpose To determine the effect of the modification of intraocular lens (IOL) surface properties on the adhesion of Staphylococcus epidermidis caused by fibronectin (FN) as the predominant proadhesive glycoprotein of the eye's initial foreign body reaction. Setting University of Saarland, Homburg/Saar, Germany. Methods Eleven IOL types were tested. The IOLs were of poly(methyl methacrylate), acrylate, or silicone. Some were surface modified with heparin or polysaccharide coating. The IOLs, unadsorbed or preadsorbed with fibronectin (FN), were incubated with [ 3 H]-thymidine-labeled S epidermidis Rp62a, and the amount of adherent microorganisms was determined. Results Attachment of S epidermidis adhesion to various types of IOLs, both unadsorbed and FN precoated, varied significantly. The attachment to highly adhesive IOLs was almost 4-fold greater than that to low-adhesive IOLs. Attachment to FN precoated IOLs was generally enhanced compared with attachment to unadsorbed IOLs. Heparin surface modification resulted in no or a modest reduction in bacterial adhesion compared with unmodified IOLs. Bacterial adhesion was highly statistically significantly less on IOLs with polysaccharide surface modification. Conclusions There was significant variability in S epidermidis adhesion to IOLs as a function of design, material, surface modification, and FN preadsorption. Application of the findings may foster new developments to further reduce the major complication in cataract surgery, infective endophthalmitis.

Astrid Sobke

Papers

Angiopoietin-2 sensitizes endothelial cells to TNF-alpha and has a crucial role in the induction of inflammation.

The extracellular adherence protein (Eap) of Staphylococcus aureus inhibits wound healing by interfering with host defense and repair mechanisms

The extracellular adherence protein from Staphylococcus aureus abrogates angiogenic responses of endothelial cells by blocking Ras activation.

Influence of fibronectin on the adherence of Staphylococcus epidermidis to coated and uncoated intraocular lenses.