| 1. |
- Ihalainen, Saara, et al.
(författare)
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Proteome analysis of cultivated vascular smooth muscle cells from a CADASIL patient
- 2007
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Ingår i: Molecular Medicine. - 1076-1551 .- 1528-3658. ; 13:5-6, s. 305-314
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Tidskriftsartikel (refereegranskat)abstract
- Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a vascular dementing disease caused by mutations in NOTCH3 gene, a majority of which are missense mutations leading to an uneven number of cysteine residues in epidermal growth factor like repeats in the extracellular domain of Notch3 receptor (N3ECD). Disease is characterized by degeneration of vascular smooth muscle cells (VSMC) and accumulation of N3ECD on the VSMCs of small and middle-sized arteries. Recent studies have demonstrated that impairment of Notch3 signaling is not the primary cause of the disease. In the present study we have characterized the protein expression pattern of a unique material of genetically genuine cultured human CADASIL VSMCs by proteomic analysis. We identified 11 differentially expressed proteins, which are involved in protein degradation and folding, contraction of VSMCs and cellular stress. Based on the results the misfolding of Notch3 seems to cause endoplasmic reticulum stress and activation of unfolded protein response leading to increased reactive oxygen species and inhibition of cell proliferation. In addition, upregulation of contractile proteins suggests an alteration in the signalling system of VSMC contraction. The accumulation of the N3ECD on the cell surface possibly upregulates the angiotensin II regulatory feedback loop and thereby enhances the readiness of the cells to respond to angiotensin II stimulation.
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| 2. |
- Iivanainen, Erika, et al.
(författare)
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Intra- and extracellular signaling by endothelial neuregulin-1
- 2007
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Ingår i: Experimental Cell Research. - : Elsevier BV. - 0014-4827 .- 1090-2422. ; 313:13, s. 2896-2909
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Tidskriftsartikel (refereegranskat)abstract
- Suppression of tumor growth by inhibition of ErbB receptor signaling is well documented. However, relatively little is known about the ErbB signaling system in the regulation of angiogenesis, a process necessary for tumor growth. We have previously shown that heparin-binding EGF-like growth factor (HB-EGF) is expressed by vascular endothelial cells (EC) and promotes endothelial recruitment of vascular smooth muscle cells (SMC). To assess whether other members of the EGF-family regulate angiogenesis, the expression of 10 EGF-like growth factors in primary ECs and SMCs was analyzed. In addition to HB-EGF, neuregulin-1 (NRG-1) was expressed in ECs in vitro and in vivo. Endothelial NRG-1 was constitutively processed to soluble extracellular and intracellular signaling fragments, and its expression was induced by hypoxia. NRG-1 was angiogenic in vivo in mouse corneal pocket and chicken chorioallantoic membrane (CAM) assays. However, consistent with the lack of NRG-1 receptors in several primary EC lines, NRG-1 did not directly stimulate cellular responses in cultured ECs. In contrast, NRG-1 promoted EC responses in vitro and angiogenesis in CAM in vivo by mechanisms dependent on VEGF-A and VEGFR-2. These results indicate that NRG-1 is expressed by ECs and regulates angiogenesis by mechanisms involving paracrine up-regulation of VEGF-A.
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