| 1. |
- Armulik, A, et al.
(författare)
-
Endothelial/pericyte interactions
- 2005
-
Ingår i: Circulation research. - 1524-4571. ; 97:6, s. 512-523
-
Tidskriftsartikel (refereegranskat)
|
|
| 2. |
|
|
| 3. |
|
|
| 4. |
- Gustafsson, Maria, 1976, et al.
(författare)
-
Retention of Low-Density Lipoprotein in Atherosclerotic Lesions of the Mouse. Evidence for a Role of Lipoprotein Lipase
- 2007
-
Ingår i: Circ Res. - 1524-4571. ; 101:8, s. 777-783
-
Tidskriftsartikel (refereegranskat)abstract
- Direct binding of apolipoprotein (apo)B-containing lipoproteins to proteoglycans is the initiating event in atherosclerosis, but the processes involved at later stages of development are unclear. Here, we investigated the importance of the apoB-proteoglycan interaction in the development of atherosclerosis over time and investigated the role of lipoprotein lipase (LPL) to facilitate low-density lipoprotein (LDL) retention at later stages of development. Atherosclerosis was analyzed in apoB transgenic mice expressing LDL with normal (control LDL) or reduced proteoglycan-binding (RK3359-3369SA LDL) activity after an atherogenic diet for 0 to 40 weeks. The initiation of atherosclerosis was delayed in mice expressing RK3359-3369SA LDL, but they eventually developed the same level of atherosclerosis as mice expressing control LDL. Retention studies in vivo showed that although higher levels of (131)I-tyramine cellobiose-labeled control LDL ((131)I-TC-LDL) were retained in nonatherosclerotic aortae compared with RK3359-3369SA (131)I-TC-LDL, the retention was significantly higher and there was no difference between the groups in atherosclerotic aortae. Lower levels of control (125)I-TC-LDL and RK3359-3369SA (125)I-TC-LDL were retained in atherosclerotic aortae from ldlr(-/-) mice transplanted with lpl(-/-) compared with lpl(+/+) bone marrow. Uptake of control LDL or RK3359-3369SA LDL into macrophages with specific expression of human catalytically active or inactive LPL was increased compared with control macrophages. Furthermore, transgenic mice expressing catalytically active or inactive LPL developed the same extent of atherosclerosis. Thus, retention of LDL in the artery wall is initiated by direct LDL-proteoglycan binding but shifts to indirect binding with bridging molecules such as LPL.
|
|
| 5. |
- Jin, Shaobo, et al.
(författare)
-
Notch signaling regulates platelet-derived growth factor receptor-beta expression in vascular smooth muscle cells
- 2008
-
Ingår i: Circulation Research. - 0009-7330 .- 1524-4571. ; 102:12, s. 1483-1491
-
Tidskriftsartikel (refereegranskat)abstract
- Notch signaling is critically important for proper architecture of the vascular system, and mutations in NOTCH3 are associated with CADASIL, a stroke and dementia syndrome with vascular smooth muscle cell (VSMC) dysfunction. In this report, we link Notch signaling to platelet-derived growth factor (PDGF) signaling, a key determinant of VSMC biology, and show that PDGF receptor (PDGFR)-beta is a novel immediate Notch target gene. PDGFR-beta expression was upregulated by Notch ligand induction or by activated forms of the Notch receptor. Moreover, upregulation of PDGFR-beta expression in response to Notch activation critically required the Notch signal integrator CSL. In primary VSMCs, PDGFR-beta expression was robustly upregulated by Notch signaling, leading to an augmented intracellular response to PDGF stimulation. In newborn Notch3-deficient mice, PDGFR-beta expression was strongly reduced in the VSMCs that later develop an aberrant morphology. In keeping with this, PDGFR-beta upregulation in response to Notch activation was reduced also in Notch3-deficient embryonic stem cells. Finally, in VSMCs from a CADASIL patient carrying a NOTCH3 missense mutation, upregulation of PDGFR-beta mRNA and protein in response to ligand-induced Notch activation was significantly reduced. In sum, these data reveal a hierarchy for 2 important signaling systems, Notch and PDGF, in the vasculature and provide insights into how dysregulated Notch signaling perturbs VSMC differentiation and function.
|
|
| 6. |
- Karpanen, Terhi, et al.
(författare)
-
Overexpression of vascular endothelial growth factor-B in mouse heart alters cardiac lipid metabolism and induces myocardial hypertrophy
- 2008
-
Ingår i: Circulation Research. - : American Heart Association. - 0009-7330 .- 1524-4571. ; 103:9, s. 1018-1026
-
Tidskriftsartikel (refereegranskat)abstract
- Vascular endothelial growth factor (VEGF)-B is poorly angiogenic but prominently expressed in metabolically highly active tissues, including the heart. We produced mice expressing a cardiac-specific VEGF-B transgene via the alpha-myosin heavy chain promoter. Surprisingly, the hearts of the VEGF-B transgenic mice showed concentric cardiac hypertrophy without significant changes in heart function. The cardiac hypertrophy was attributable to an increased size of the cardiomyocytes. Blood capillary size was increased, whereas the number of blood vessels per cell nucleus remained unchanged. Despite the cardiac hypertrophy, the transgenic mice had lower heart rate and blood pressure than their littermates, and they responded similarly to angiotensin II-induced hypertension, confirming that the hypertrophy does not compromise heart function. Interestingly, the isolated transgenic hearts had less cardiomyocyte damage after ischemia. Significantly increased ceramide and decreased triglyceride levels were found in the transgenic hearts. This was associated with structural changes and eventual lysis of mitochondria, resulting in accumulation of intracellular vacuoles in cardiomyocytes and increased death of the transgenic mice, apparently because of mitochondrial lipotoxicity in the heart. These results suggest that VEGF-B regulates lipid metabolism, an unexpected function for an angiogenic growth factor.
|
|
| 7. |
|
|
| 8. |
- Lai, En Yin, et al.
(författare)
-
Adenosine restores angiotensin II-induced contractions by receptor-independent enhancement of calcium sensitivity in renal arterioles
- 2006
-
Ingår i: Circulation Research. - 0009-7330 .- 1524-4571. ; 99:10, s. 1117-1124
-
Tidskriftsartikel (refereegranskat)abstract
- Adenosine is coupled to energy metabolism and regulates tissue blood flow by modulating vascular resistance. In this study, we investigated isolated, perfused afferent arterioles of mice, which were subjected to desensitization during repeated applications of angiotensin II. Exogenously applied adenosine restores angiotensin II-induced contractions by increasing calcium sensitivity of the arterioles, along with augmented phosphorylation of the regulatory unit of the myosin light chain. Adenosine restores angiotensin II-induced contractions via intracellular action, because inhibition of adenosine receptors do not prevent restoration, but inhibition of NBTI sensitive adenosine transporters does. Restoration was prevented by inhibition of Rho-kinase, protein kinase C, and the p38 mitogen-activated protein kinase, which modulate myosin light chain phosphorylation and thus calcium sensitivity in the smooth muscle. Furthermore, adenosine application increased the intracellular ATP concentration in LuciHEK cells. The results of the study suggest that restoration of the angiotensin II-induced contraction by adenosine is attributable to the increase of the calcium sensitivity by phosphorylation of the myosin light chain. This can be an important component of vascular control during ischemic and hypoxic conditions. Additionally, this mechanism may contribute to the mediation of the tubuloglomerular feedback by adenosine in the juxtaglomerular apparatus of the kidney.
|
|
| 9. |
- Lidén, Åsa, et al.
(författare)
-
Platelet-derived growth factor BB-mediated normalization of dermal interstitial fluid pressure after mast cell degranulation depends on beta3 but not beta1 integrins
- 2006
-
Ingår i: Circulation Research. - 0009-7330 .- 1524-4571. ; 98:5, s. 635-641
-
Tidskriftsartikel (refereegranskat)abstract
- Interstitial fluid pressure (PIF) is one of the determinants of transcapillary fluid flux and thereby interstitial fluid volume. Cell-mediated control of PIF regulates fluid content in the loose interstitial connective tissues that surround the capillary bed. To maintain a normal PIF in dermis, β1 integrins mediate the tensile strength applied by connective tissue cells on the extracellular matrix. Platelet-derived growth factor (PDGF)-BB normalizes anaphylaxis-induced reduction of PIF. Anti–β3 integrin IgG and a cyclic RGD peptide that inhibits the αVβ3 integrin blocked the ability of PDGF-BB to normalize the lowered PIF resulting from mast cell degranulation. PDGF-BB was unable to normalize PIF lowered as a result of mast cell degranulation in β3-negative mice. Monoclonal anti–β3 integrin IgG had no effect on PIF in normal mouse dermis. In contrast, administration of anti–β1 integrin IgM lowered PIF in normal dermis but had no effect on PDGF-BB–induced normalization of PIF after anaphylaxis. Furthermore, collagen gel contraction mediated by wild-type mouse embryonal fibroblasts were only marginally affected by function-blocking anti–β1 integrin antibodies, especially in the presence of PDGF-BB. In contrast, contraction mediated by αV-negative mouse embryonic fibroblasts was completely blocked by anti–β1 integrin antibodies, even after stimulation with PDGF-BB. These results show a previously unrecognized in vivo function for the αVβ3 integrin, as a participant in the control of PIF during inflammatory reactions. Furthermore, our data demonstrate that PDGF-BB induces connective tissue cells to generate tensile forces via αVβ3 during such reactions.
|
|
| 10. |
|
|
