supramaximal-intensity-hypoxic-exercise-vascular-function-assessment

Supramaximal Intensity Hypoxic Exercise and Vascular Function Assessment in Mice

Exercise training is an important strategy for maintaining health and preventing many chronic diseases. It is the first line of treatment recommended by ...

Lausanne University Hospital (CHUV)

Dyslipidemia is a known risk factor for cardiovascular diseases and may associate with renal injury. Using mouse models with various degrees of hypercholesterolemia and hypertryliceridemia, we investigated the effects of lipids on the renin-angiotensin system (RAS). ApoE-/- mice were fed either a high fat diet (HF-ApoE-/-; mice developed hypertriglyceridemia and severe hypercholesterolemia) or regular chow (R-ApoE(-/-); mice developed less severe hypercholesterolemia only). Renal histopathology in the HF-ApoE-/- revealed massive lipid accumulation especially at the glomerular vascular pole. In these mice plasma renin concentration was significantly reduced (489+/-111 ng/(ml h) versus 1023+/-90 ng/(ml h) in R-ApoE-/- mice) and blood pressure was consequently significantly lower than in R-ApoE-/- (104+/-2 mmHg versus 115+/-2 mmHg, respectively). A model of renin-dependent renovascular hypertension (two-kidney, one clip) was generated and HF-ApoE-/- mice proved unable to increase renin secretion, and blood pressure, in response to diminished renal perfusion as compared to regular chow fed mice (665+/-90 ng/(ml h) versus 2393+/-372 ng/(ml h), respectively and 106+/-3 mmHg versus 140+/-2 mmHg, respectively). Hypertriglyceridemia and severe hypercholesterolemia are associated with renal lipid deposition and impaired renin secretion in ApoE-/- mice exposed to high fat diet. These observations further characterize the phenotype of this widely used mouse model and provide a rationale for the use of these mice to study lipid induced organ damage.

Severe hyperlipidemia causes impaired renin-angiotensin system function in apolipoprotein E deficient mice.

Atherosclerosis is an insidious and complex disease of large- and medium-sized arteries. The primum movens of the disease is characterized by co-localization of lipids, inflammatory cells, and fibrous elements within the intima of vessels. Starting as a "fatty streak," the disease evolves over decades into complex lesions that can progress toward a stable or a vulnerable plaque. During the past decade, we have become familiar with the features of the vulnerable plaque; however, the mechanisms that cause a stable plaque to change into a vulnerable lesion with its dramatic clinical outcome still remain largely unknown. There is good evidence from epidemiologic, experimental, and clinical studies that the renin-angiotensin system, via its active peptide angiotensin II, may contribute to atherosclerosis development and progression, not only by increasing blood pressure but also through multiple direct effects. Moreover, recent studies have shown a potential role for angiotensin II as a mediator of plaque vulnerability.

The renin-angiotensin system and atherosclerosis.

Heparin is the drug of choice for the treatment or the prevention of thromboembolic disease during pregnancy. However, treatment options are limited when heparin cannot be used because of hypersensitivity skin reactions. Despite the recent availability of new anticoagulant agents, data relating to their use during pregnancy are lacking. This report describes the successful management with fondaparinux, during 150 days, of a pregnant patient with protein S deficiency and prior deep vein thrombosis (DVT) who developed heparin and danaparoid hypersensitivity.

Fondaparinux is a safe alternative in case of heparin intolerance during pregnancy.

Venous thromboembolism is a complex disease resulting from the interactions of several risk factors from diverse origins: genetic, environmental and behavioral. Numerous studies have evidenced an association between genetic thrombophilia defects and venous thromboembolism. However, the clinical relevance of genetic thrombophilia to recurrent venous thromboembolism is not clear and the risks of long-term anticoagulant treatment usually outweigh any benefits of hereditary thrombophilia screening. Therefore, in everyday clinical practice (outside of research protocols) hereditary thrombophilia screening should be performed only in cases where such testing is likely to influence patient management.

Hereditary thrombophilia and venous thromboembolism: critical evaluation of the clinical implications of screening.

Endothelial progenitor-derived cells (EPC) are a cell therapy tool in peripheral arterial disease and for re-endothelialization of bypasses and stents.

Characterization of human late outgrowth endothelial progenitor-derived cells under various flow conditions.

Despite recent advances in pharmacological research and microsurgery, lymphoedema remains an incurable disease that deeply affects quality of life. There is an urgent need for innovative approaches to restore continuous lymph flow in affected tissues. To this end, the efficacy of a subcutaneously implanted draining device in reducing lymphoedema volume in a rat hindlimb lymphoedema model was tested.

First Successful Experimental Implantation of a Drainage Device to Reduce Lymphoedema in a Rat Lymphoedema Model.

Angiotensin (Ang) II triggers vulnerable atherosclerotic plaque development. Bone marrow (BM)-derived cells are key players in atherogenesis but whether Ang II induces plaque vulnerability directly through Ang II type 1 receptor (AT1R) activation on these cells remains to be clarified. In the present study, we investigated whether a lack of AT1R on BM-derived cells might affect Ang II-mediated vulnerable plaque development. The 2-kidney, 1-clip (2K1C) model (Ang II-dependent mouse model of advanced atherosclerosis and vulnerable plaques) was generated in ApoE mice transplanted with AT1aR or AT1aR BM. Plasma cholesterol as well as hepatic mRNA expression levels of genes involved in cholesterol metabolism were significantly lower in 2K1C mice transplanted with AT1aR BM than in controls. Atherosclerotic lesions were significantly smaller in AT1aR BM 2K1C mice (-79% in the aortic sinus and -71% in whole aorta compared to controls). Plaques from AT1aR BM 2K1C mice exhibited reduced lipid core/fibrous cap and macrophage/smooth muscle cells ratios (-82% and -88%, respectively), and increased collagen content (+70%), indicating a more stable phenotype. Moreover, aortic mRNA levels of pro-inflammatory cytokines IL-12p35, IL-1β, and TNF-α were significantly reduced in AT1aR BM 2K1C mice. No significant differences in either the number of circulating Ly6C inflammatory monocytes and Ly6C resident anti-inflammatory monocyte subsets, or in mRNA levels of aortic M1 or M2 macrophage markers were observed between the two groups. No significant differences were observed in splenic mRNA levels of T cell subsets (Th1, Th2, Th17 and Treg) markers between the two groups. In conclusion, direct AT1R activation by Ang II on BM-derived cells promotes hepatic mRNA expression of cholesterol-metabolism-related genes and vascular mRNA expression of pro-inflammatory cytokines that may lead to plaque instability.

Article	Year
Severe hyperlipidemia causes impaired renin-angiotensin system function in apolipoprotein E deficient mice. Atherosclerosis\| PubMed ID: 16112122	2006
The renin-angiotensin system and atherosclerosis. Current hypertension reports\| PubMed ID: 16600159	2006
Fondaparinux is a safe alternative in case of heparin intolerance during pregnancy. Blood\| PubMed ID: 16645165	2006
Hereditary thrombophilia and venous thromboembolism: critical evaluation of the clinical implications of screening. European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery\| PubMed ID: 17588784	2007
Characterization of human late outgrowth endothelial progenitor-derived cells under various flow conditions. Journal of vascular research\| PubMed ID: 21625177	2011
First Successful Experimental Implantation of a Drainage Device to Reduce Lymphoedema in a Rat Lymphoedema Model. European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery\| PubMed ID: 29804748	2018
Activation of Bone Marrow-Derived Cells Angiotensin (Ang) II Type 1 Receptor by Ang II Promotes Atherosclerotic Plaque Vulnerability. International journal of molecular sciences\| PubMed ID: 30181481	2018

Lucia Mazzolai

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