Angiogenesis in mature tissues is a complex process involving dissolution of the existing matrix, migration and proliferation of endothelial cells, formation and maturation of new vascular structure and finally deposition of new extracellular matrix. Recent from our laboratory as well as others has demonstrated that some of these growth factors including VEGF and FGFs can induce functionally significant angiogenesis when used in the setting of myocardial ischemia. The mechanisms of these effects are, however, poorly understood. In particular, our as well s other studies suggest a central role of nitric oxide (NO) in the mediation of many effects of VEGF including vasomotion, changes in vascular permeability and stimulation of endothelial cell growth. These biological effects of VEGF together, with the capacity of this cytokine to induce an inflammatory response appear to be at the core of its ability to initiate and sustain angiogenesis. In order to study these issues and to address the role of cell type specific of gene expression in angiogenesis, we propose to take advantage of mice lines with knockout of iNOS and eNOS as well as macrophage-deficient mice. The availability of these mutants in combination with established mouse models of angiogenesis and inducible transgenic tissue specific expression of desired genes, provide a powerful combination in the study of the molecular mechanism of angiogenesis. The project will concentrate on the following two Specific Aims: I. Role of NO in mediation of VEGF-induced effects in coronary circulation; II. Cell type specificity of VEGF-dependent NO generation. Taken together these two Aims will provide new information regarding fundamental biological processes involved in regulation of angiogenic response and lead to better understand of the molecular mechanism of VEGF action.
| Chen, Dongying; Simons, Michael (2018) Reprogramming the Endocardium: Trials and Tribulations. Circ Res 122:913-915 |
| Zhang, Feng; Zarkada, Georgia; Han, Jinah et al. (2018) Lacteal junction zippering protects against diet-induced obesity. Science 361:599-603 |
| Yu, Pengchun; Wu, Guosheng; Lee, Heon-Woo et al. (2018) Endothelial Metabolic Control of Lymphangiogenesis. Bioessays 40:e1700245 |
| Kofler, Natalie; Corti, Federico; Rivera-Molina, Felix et al. (2018) The Rab-effector protein RABEP2 regulates endosomal trafficking to mediate vascular endothelial growth factor receptor-2 (VEGFR2)-dependent signaling. J Biol Chem 293:4805-4817 |
| Dejana, Elisabetta; Hirschi, Karen K; Simons, Michael (2017) The molecular basis of endothelial cell plasticity. Nat Commun 8:14361 |
| Yu, Pengchun; Wilhelm, Kerstin; Dubrac, Alexandre et al. (2017) FGF-dependent metabolic control of vascular development. Nature 545:224-228 |
| Corti, Federico; Simons, Michael (2017) Modulation of VEGF receptor 2 signaling by protein phosphatases. Pharmacol Res 115:107-123 |
| Chen, Pei-Yu; Simons, Michael (2016) When endothelial cells go rogue. EMBO Mol Med 8:1-2 |
| Kofler, Natalie; Simons, Michael (2016) The expanding role of neuropilin: regulation of transforming growth factor-? and platelet-derived growth factor signaling in the vasculature. Curr Opin Hematol 23:260-7 |
| Chen, Pei-Yu; Qin, Lingfeng; Li, Guangxin et al. (2016) Smooth muscle FGF/TGF? cross talk regulates atherosclerosis progression. EMBO Mol Med 8:712-28 |
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