Vascular remodelling in the pathogenesis of idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible fibrosing interstitial pneumonia of unknown aetiology that usually leads to respiratory failure and death within 5 years of diagnosis. Alveolar epithelial cell injury, disruption of alveolar capillary membrane integrity and abnormal vascular repair and remodelling have all been proposed as possible pathogenic mechanisms. This review summarizes our current knowledge of the abnormalities in vascular remodelling observed in IPF and highlights several of the cytokines thought to play a pathogenic role, which may ultimately prove to be future therapeutic targets.

The Wnt pathway and the roles for its antagonists, DKKS, in angiogenesis.

The Wnt signaling pathway is involved in a wide range of developmental and physiological processes, such as cell fate specification, tissue morphogenesis, and homeostasis. Thus, its dysregulation has been found in multiple diseases, including some cardiovascular disorders. The loss or gain of function of Wnt pathway components results in abnormal vascular development and angiogenesis. Further study has revealed that Wnt signaling in endothelial cells appears to contribute to vascular morphogenesis and endothelial cell specification. Owing to the significance of Wnt signaling in angiogenesis, Wnt antagonists have been considered potential treatments for neovascular disorders. In line with this, members of the Dkk protein family (Dkks), well-known Wnt antagonists, have been recently found to regulate angiogenesis. This review summarizes our present knowledge of the roles of Wnt signaling and Wnt antagonists, particularly Dkks, in angiogenic regulation and explores the therapeutic potential of Wnt antagonists.

Cancer CXC chemokine networks and tumour angiogenesis.

Chemokines have pleiotropic effects in regulating immunity, angiogenesis, stem cell trafficking, and mediating organ-specific metastases of cancer. In the context of angiogenesis, the CXC chemokine family is a unique group of cytokines known for their ability to behave in a disparate manner in the regulation of angiogenesis. The glutamic acid-leucine-arginine (ELR+) CXC chemokines are potent promoters of angiogenesis, and mediate their angiogenic activity via signal-coupling of CXCR2 on endothelium. By contrast, members of the CXC chemokine family, such as platelet factor-4 (PF4; CXCL4) and interferon-inducible CXC chemokines are potent inhibitors of angiogenesis, and use CXCR3 on endothelium to mediate their angiostatic activity. This review will discuss the biology of CXC chemokines in the context of angiogenesis related to cancer.

Matrix revolutions: "tails" of basement-membrane components with angiostatic functions.

Angiogenesis, the creation of neovasculature from native blood vessels, is a prerequisite for many physiological and pathological processes. Recently, C-terminal tail fragments of several basement-membrane proteins such as endostatin, tumstatin and endorepellin have been shown to inhibit angiogenesis. Although there seems to be little or no homology among them, a common theme is that these fragments modulate endothelial cells by distinct interactions with integrins and activate distinct intracellular signaling cascades that often lead to disruption of the actin cytoskeleton. In this article, we focus on recent advances regarding the mechanism of action of these angiostatic fragments and the emerging concept of similarities among them, with the underlying premise that appreciating these similarities might lead to improved therapeutics.

[Hypoxia and angiogenesis in rheumatic diseases]. / Hypoxie und Angiogenese in rheumatischen Erkrankungen.

The important role of angiogenesis for the pathogenesis of most tumors has gained much interest into the mechanisms of new vessel formation during recent years. Hypoxia induces angiogenesis via stabilization of the transcription factor HIF-1alpha. After dimerization of HIF-1alpha with HIF-1beta/ARNT, HIF-1 binds to the hypoxia-responsive elements in the regulatory regions of proangiogenic molecules such as VEGF. Hypoxia-mediated angiogenesis also plays a part in the pathogenesis of rheumatoid arthritis. For instance, intraarticular application of the angiostatic molecule angiostatin reduces the severity of collagen-induced arthritis in mice. Moreover, recent data indicate that the expression of HIF-1alpha in myeloid cells is important for the initiation of the inflammatory infiltrate in rheumatoid arthritis. In contrast to rheumatoid arthritis, the therapeutic goal in systemic sclerosis (SSc) is the formation of new vessels rather than the inhibition of angiogenesis. Surprisingly, several proangiogenic factors such as VEGF or MCP-1 (CCL-2) are overexpressed in the skin of patients with SSc despite the reduction in the capillary density. The role of these findings for the defective angiogenesis in SSc is currently investigated in our laboratory.