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IntroductionAngiogenesis is a critical process in physiologic and pathologic conditions, including embryo development, wound healing, tumor progression, and inflammatory diseases. 1 Inflammation and angiogenesis are closely associated, and pathologic angiogenesis has been implicated in the development of chronic inflammatory diseases. Interplay between inflammation and angiogenesis is mediated largely by cytokines, chemokines, and growth factors. Some of these molecules, including vascular endothelial growth factor (VEGF), induce endothelial permeability, allowing the infiltration of leukocytes to inflammatory sites, resulting in tissue damage. 2 Interleukin-33 (IL-33) is a newly identified cytokine of the IL-1 family, which also includes the inflammatory cytokines IL-1␣, It has been shown to signal via ST2 receptor. 4 IL-33 expression is broadly detected in various tissues, including stomach, lung, spinal cord, brain, and skin, as well as in cells, including smooth muscle cells and epithelial cells lining bronchus and small airways. 4 Notably, IL-33 expression is induced by IL-1␤ and tumor necrosis factor-␣ (TNF-␣) in lung and dermal fibroblast and, to a lesser extent, by macrophage activation. 4 IL-33 treatment has been shown to induce T-helper (Th) type 2 responses in mice as indicated by an increase in Th2 cytokine production and serum immunoglobulin. Systemic treatment of mice with IL-33 results in pathologic changes in the lung and the digestive tract. In the lung, vascular changes accompanied with eosinophilic and mononuclear infiltrates were observed in small muscular arteries. 4 Recently, functions of IL-33 in cardiovascular diseases have been reported. For example, IL-33 can reduce the development of atherosclerosis in apolipoprotein E Ϫ/Ϫ mice on a high-fat diet. 5 Furthermore, IL-33/ST2 complexes also have been shown to activate cardioprotective signaling pathways. 6 IL-33 is produced as a 30-kDa precursor protein that is cleaved in vitro by caspase-1, releasing the mature 18-kDa form. 4 Upon binding to the ST2 receptor, IL-33 promotes the activation of nuclear factor (NF)-B and mitogen-activated protein kinase (MAPK), leading to increased transcription of Th2 cytokines. 4 The ST2 receptor, a member of IL-1 receptor family, has long been known as an orphan receptor. Despite its structural and functional similarity to IL-1 receptor family, the ST2 receptor does not bind to IL-1␣ or IL-1␤ or other members of the IL-1 family. Two isoforms, a soluble (sST2) and a membrane bound form (ST2L), are produced through differential mRNA processing. 7,8 ST2L is expressed mainly in mast cells and Th2 cells. 7,8 Both ST2 forms also are expressed in freshly isolated human umbilical vein endothelial cells (HUVECs), and they are up-regulated by proinflammatory stimuli such as TNF, IL-1␣, and IL-1␤. 9 Nitric oxide (NO) production in endothelial cells (ECs) is transiently regulated by multiple inflammatory angiogenic factors such as VEGF and angiopoietin-1. 10,11 NO, in turn, modulates the angiogenic function of these ...

Neovessel formation is a complex process governed by the orchestrated action of multiple factors that regulate EC specification and dynamics within a growing vascular tree. These factors have been widely exploited to develop therapies for angiogenesis-related diseases such as diabetic retinopathy and tumor growth and metastasis. WNT signaling has been implicated in the regulation and development of the vascular system, but the detailed mechanism of this process remains unclear. Here, we report that Dickkopf1 (DKK1) and Dickkopf2 (DKK2), originally known as WNT antagonists, play opposite functional roles in regulating angiogenesis. DKK2 induced during EC morphogenesis promoted angiogenesis in cultured human endothelial cells and in in vivo assays using mice. Its structural homolog, DKK1, suppressed angiogenesis and was repressed upon induction of morphogenesis. Importantly, local injection of DKK2 protein significantly improved tissue repair, with enhanced neovascularization in animal models of both hind limb ischemia and myocardial infarction. We further showed that DKK2 stimulated filopodial dynamics and angiogenic sprouting of ECs via a signaling cascade involving LRP6-mediated APC/Asef2/Cdc42 activation. Thus, our findings demonstrate the distinct functions of DKK1 and DKK2 in controlling angiogenesis and suggest that DKK2 may be a viable therapeutic target in the treatment of ischemic vascular diseases.

Capsiate, a nonpungent capsaicin analogue, and its dihydroderivative dihydrocapsiate are the major capsaicinoids of the nonpungent red pepper cultivar CH

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