Microvascular disease in chronic kidney disease: the base of the iceberg in cardiovascular comorbidity.

Chronic kidney disease (CKD) is a relentlessly progressive disease with a very high mortality mainly due to cardiovascular complications. Endothelial dysfunction is well documented in CKD and permanent loss of endothelial homeostasis leads to progressive organ damage. Most of the vast endothelial surface area is part of the microcirculation, but most research in CKD-related cardiovascular disease (CVD) has been devoted to macrovascular complications. We have reviewed all publications evaluating structure and function of the microcirculation in humans with CKD and animals with experimental CKD. Microvascular rarefaction, defined as a loss of perfused microvessels resulting in a significant decrease in microvascular density, is a quintessential finding in these studies. The median microvascular density was reduced by 29% in skeletal muscle and 24% in the heart in animal models of CKD and by 32% in human biopsy, autopsy and imaging studies. CKD induces rarefaction due to the loss of coherent vessel systems distal to the level of smaller arterioles, generating a typical heterogeneous pattern with avascular patches, resulting in a dysfunctional endothelium with diminished perfusion, shunting and tissue hypoxia. Endothelial cell apoptosis, hypertension, multiple metabolic, endocrine and immune disturbances of the uremic milieu and specifically, a dysregulated angiogenesis, all contribute to the multifactorial pathogenesis. By setting the stage for the development of tissue fibrosis and end organ failure, microvascular rarefaction is a principal pathogenic factor in the development of severe organ dysfunction in CKD patients, especially CVD, cerebrovascular dysfunction, muscular atrophy, cachexia, and progression of kidney disease. Treatment strategies for microvascular disease are urgently needed.

CardioScape mapping the cardiovascular funding landscape in Europe.

Aims: The burden of cardiovascular disease is increasing worldwide, which has to be reflected by cardiovascular (CV) research in Europe. CardioScape, a FP7 funded project initiated by the European Society of Cardiology (ESC), identified where CV research is performed, how it is funded and by whom. It could be transformed into an on-line and up-to-date resource of great relevance for researchers, funding bodies and policymakers and could be a role model for mapping CV research funding in Europe and beyond. Methods and results: Relevant funding bodies in 28 European Union (EU) countries were identified by a multistep process involving experts in each country. Projects above a funding threshold of 100 k€ during the period 2010-2012 were included using a standard questionnaire. Results were classified by experts and an adaptive text analysis software to a CV-research taxonomy, integrating existing schemes from ESC journals and congresses. An on-line query portal was set up to allow different users to interrogate the database according to their specific viewpoints. Conclusion: CV-research funding varies strongly between different nations with the EU providing 37% of total available project funding and clear geographical gradients exist. Data allow in depth comparison of funding for different research areas and led to a number of recommendations by the consortium. CardioScape can support CV research by aiding researchers, funding agencies and policy makers in their strategic decisions thus improving research quality if CardioScape strategy and technology becomes the basis of a continuously updated and expanded European wide publicly accessible database.

Shear stress increases endothelial hyaluronan synthase 2 and hyaluronan synthesis especially in regard to an atheroprotective flow profile.

Recent studies revealed that in vivo the inner blood vessel surface is lined with an endothelial surface layer at least 0.5 µm thick, which serves as an aegis, protecting the vessel wall from arteriosclerosis. Hyaluronan seems to be a constitutive component in regard to the atheroprotective properties of this surface structure. It has been shown that arterial pulsatile laminar blood flow increases the thickness of this surface layer in vivo, while it is significantly reduced at atheroprone regions with disturbed flow. This study was undertaken to reveal whether endothelial hyaluronan synthesis via hyaluronan synthase 2 (HAS2) can be changed by different shear stress conditions in vitro, especially in regard to an undisturbed, arterial-like pulsatile flow profile. Human umbilical vein endothelial cells, exposed to constant or pulsatile shear stress in a cone-and-plate system, were analysed for HAS2 expression by real-time RT-PCR and immunoblotting, and for hyaluronan by ELISA. Hyaluronan synthase 2 mRNA and protein were found to be transiently increased in a shear stress-dependent manner via the phosphatidylinositol 3-kinase-Akt pathway. Especially pulsatile, arterial-like shear stress conditions induced enzyme and hyaluronan effectively, while lower shear stress that continuously changed its direction did not induce any differences in comparison with control cultures not exposed to shear stress. These experiments provide a link between the production of a constitutive component of the endothelial surface layer by endothelial cells and blood flow.

Chronic kidney disease induces a systemic microangiopathy, tissue hypoxia and dysfunctional angiogenesis.

Chronic kidney disease (CKD) is associated with excessive mortality from cardiovascular disease (CVD). Endothelial dysfunction, an early manifestation of CVD, is consistently observed in CKD patients and might be linked to structural defects of the microcirculation including microvascular rarefaction. However, patterns of microvascular rarefaction in CKD and their relation to functional deficits in perfusion and oxygen delivery are currently unknown. In this in-vivo microscopy study of the cremaster muscle microcirculation in BALB/c mice with moderate to severe uremia, we show in two experimental models (adenine feeding or subtotal nephrectomy), that serum urea levels associate incrementally with a distinct microangiopathy. Structural changes were characterized by a heterogeneous pattern of focal microvascular rarefaction with loss of coherent microvascular networks resulting in large avascular areas. Corresponding microvascular dysfunction was evident by significantly diminished blood flow velocity, vascular tone, and oxygen uptake. Microvascular rarefaction in the cremaster muscle paralleled rarefaction in the myocardium, which was accompanied by a decrease in transcription levels not only of the transcriptional regulator HIF-1α, but also of its target genes Angpt-2, TIE-1 and TIE-2, Flkt-1 and MMP-9, indicating an impaired hypoxia-driven angiogenesis. Thus, experimental uremia in mice associates with systemic microvascular disease with rarefaction, tissue hypoxia and dysfunctional angiogenesis.

Regulation of Foxo-1 and the angiopoietin-2/Tie2 system by shear stress.

Transcription factor Foxo-1 can be inactivated via Akt-mediated phosphorylation. Since shear stress activates Akt, we determined whether Foxo-1 and the Foxo-1-dependent, angiogenesis-related Ang-2/Tie2-system are influenced by shear stress in endothelial cells. Expression of Foxo-1 and its target genes p27Kip1 and Ang-2 was decreased under shear stress (6dyn/cm(2), 24h), nuclear exclusion of Foxo-1 by phosphorylation increased. eNOS and Tie2 were upregulated. No effects on Ang-1 expression were detected. In conclusion, Foxo-1 and Ang-2/Tie2 are part of the molecular response to shear stress, which may regulate angiogenesis.