Корекція гемореологічних порушень у хворих на цукровий діабет з використанням низькоінтенсивного лазерного опромінення крові

In mammals, the homeodomain transcription factor Prox1 acts as the central regulator of lymphatic cell fate. Its restricted expression in a subset of cardinal vein cells leads to a switch towards lymphatic specification and hence represents a prerequisite for the initiation of lymphangiogenesis. Murine Prox1-null embryos lack lymphatic structures, and sustained expression of Prox1 is indispensable for the maintenance of lymphatic cell fate even at adult stages, highlighting the unique importance of this gene for the lymphatic lineage. Whether this pre-eminent role of Prox1 within the lymphatic vasculature is conserved in other vertebrate classes has remained unresolved, mainly owing to the lack of availability of loss-of-function mutants. Here, we re-examine the role of Prox1a in zebrafish lymphangiogenesis. First, using a transgenic reporter line, we show that prox1a is initially expressed in different endothelial compartments, becoming restricted to lymphatic endothelial cells only at later stages. Second, using targeted mutagenesis, we show that Prox1a is dispensable for lymphatic specification and subsequent lymphangiogenesis in zebrafish. In line with this result, we found that the functionally related transcription factors Coup-TFII and Sox18 are also dispensable for lymphangiogenesis. Together, these findings suggest that lymphatic commitment in zebrafish and mice is controlled in fundamentally different ways

Vascular Hypothesis of Alzheimer Disease: Topical Review of Mouse Models

Alzheimer disease (AD) is marked by profound neurodegeneration, neuroinflammation, and cognitive decline. Pathologically, AD is characterized by the accumulation of extracellular amyloid and intraneuronal tangles, consisting of hyperphosphorylated tau. To date, factors leading to disease onset and progression are still an important topic of investigation. Various epidemiological studies revealed cardiovascular disease as an important contributor to the development and progression of AD, leading to the so-called vascular hypothesis. Vascular risk factors, such as hypertension, diabetes, and hyperhomocysteinemia, are associated with a significantly increased chance of developing AD, suggesting an additive or even synergistic effect. These vascular risk factors are often linked to a reduction in cerebral blood flow and the resulting chronic cerebral hypoperfusion is suggested to play a key role in the onset of AD. However, the causal effects of such vascular risk factors for AD onset remain largely unknown. Evidence from animal studies support that chronic cerebral hypoperfusion induction causes a strong aggravation of AD-related pathology, but a comprehensive overview of how the various cardiovascular disease risk factors contribute to disease is lacking. Therefore, we here critically review current literature, to unravel the existing evidence derived from in vivo mouse studies and define the role of cardiovascular disease and chronic cerebral hypoperfusion in AD development. We conclude that, although many aspects of the vascular hypothesis are well supported by observational studies, in-depth mechanistic studies and well-designed randomized controlled trials are highly needed to establish temporal and causal relationships. Described new insights can have major prospective potential for therapeutic interventions

Sox7 controls arterial specification in conjunction with hey2 and efnb2 function

SoxF family members have been linked to arterio-venous specification events and human pathological conditions, but in contrast to Sox17 and Sox18, a detailed in vivo analysis of a Sox7 mutant model is still lacking. In this study we generated zebrafish sox7 mutants to understand the role of Sox7 during vascular development. By in vivo imaging of transgenic zebrafish lines we show that sox7 mutants display a short circulatory loop around the heart as a result of aberrant connections between the lateral dorsal aorta (LDA) and either the venous primary head sinus (PHS) or the common cardinal vein (CCV). In situ hybridization and live observations in flt4:mCitrine transgenic embryos revealed increased expression levels of flt4 in arterial endothelial cells at the exact location of the aberrant vascular connections in sox7 mutants. An identical circulatory short loop could also be observed in newly generated mutants for hey2 and efnb2. By genetically modulating levels of sox7, hey2 and efnb2 we demonstrate a genetic interaction of sox7 with hey2 and efnb2. The specific spatially confined effect of loss of Sox7 function can be rescued by overexpressing the Notch intracellular domain (NICD) in arterial cells of sox7 mutants, placing Sox7 upstream of Notch in this aspect of arterial development. Hence, sox7 levels are crucial in arterial specification in conjunction with hey2 and efnb2 function, with mutants in all three genes displaying shunt formation and an arterial block

Profiling the unique protective properties of intracranial arterial endothelial cells

Cardiovascular disorders, like atherosclerosis and hypertension, are increasingly known to be associated with vascular cognitive impairment (VCI). In particular, intracranial atherosclerosis is one of the main causes of VCI, although plaque development occurs later in time and is structurally different compared to atherosclerosis in extracranial arteries. Recent data suggest that endothelial cells (ECs) that line the intracranial arteries may exert anti-atherosclerotic effects due to yet unidentified pathways. To gain insights into underlying mechanisms, we isolated post-mortem endothelial cells from both the intracranial basilar artery (BA) and the extracranial common carotid artery (CCA) from the same individual (total of 15 individuals) with laser capture microdissection. RNA sequencing revealed a distinct molecular signature of the two endothelial cell populations of which the most prominent ones were validated by means of qPCR. Our data reveal for the first time that intracranial artery ECs exert an immune quiescent phenotype. Secondly, genes known to be involved in the response of ECs to damage (inflammation, differentiation, adhesion, proliferation, permeability and oxidative stress) are differentially expressed in intracranial ECs compared to extracranial ECs. Finally, Desmoplakin (DSP) and Hop Homeobox (HOPX), two genes expressed at a higher level in intracranial ECs, and Sodium Voltage-Gated Channel Beta Subunit 3 (SCN3B), a gene expressed at a lower level in intracranial ECs compared to extracranial ECs, were shown to be responsive to shear stress and/or hypoxia. With our data we present a set of intracranial-specific endothelial genes that may contribute to its protective phenotype, thereby supporting proper perfusion and consequently may preserve cognitive function. Deciphering the molecular regulation of the vascular bed in the brain may lead to the identification of novel potential intervention strategies to halt vascular associated disorders, such as atherosclerosis and vascular cognitive dysfunction

Cgnl1, an endothelial junction complex protein, regulates GTPase mediated angiogenesis

Aims The formation of cell-cell and cell-extra cellular matrix (ECM) contacts by endothelial cells (ECs) is crucial for the stability and integrity of a vascular network. We previously identified cingulin-like 1 (Cgnl1) in a transcriptomic screen for new angiogenic modulators. Here we aim to study the function of the cell-cell junction associated protein Cgnl1 during vessel formation. Methods and results Unlike family member cingulin, Cgnl1 expression is enriched in ECs during vascular growth. Cgnl1 is important for the formation of multicellular tubule structures, as shown in vitro using loss-of function assays in a 3D matrix co-culture system that uses primary human ECs and supporting mural cells. Further studies revealed that Cgnl1 regulates vascular growth by promoting Ve-cadherin association with the actin cytoskeleton, thereby stabilizing adherens junctions. Cgnl1 also regulates focal adhesion assembly in response to ECM contact, promoting vinculin and paxillin recruitment and focal adhesion kinase signalling. In vivo, we demonstrate in a postnatal retinal vascular development model in mice that Cgnl1 function is crucial for sustaining neovascular growth and stability. Conclusions Our data demonstrate a functional relevance for Cgnl1 as a defining factor in new vessel formation both in vitro and in vivo

THSD1 preserves vascular integrity and protects against intraplaque haemorrhaging in ApoE-/- mice

Aims: Impairment of the endothelial barrier leads to microvascular breakdown in cardiovascular disease and is involved in intraplaque haemorrhaging and the progression of advanced atherosclerotic lesions that are vulnerable to rupture. The exact mechanism that regulates vascular integrity requires further definition. Using a microarray screen for angiogenesis-Associated genes during murine embryogenesis, we identified thrombospondin type I domain 1 (THSD1) as a new putative angiopotent factor with unknown biological function. We sought to characterize the role of THSD1 in endothelial cells during vascular development and cardiovascular disease. Methods and results: Functional knockdown of Thsd1 in zebrafish embryos and in a murine retina vascularization model induced severe haemorrhaging without affecting neovascular growth. In human carotid endarterectomy specimens, THSD1 expression by endothelial cells was detected in advanced atherosclerotic lesions with intraplaque haemorrhaging, but was absent in stable lesions, implying involvement of THSD1 in neovascular bleeding. In vitro, stimulation with pro-Atherogenic factors (3% O2and TNFα) decreased THSD1 expression in human endothelial cells, whereas stimulation with an anti-Atherogenic factor (IL10) showed opposite effect. Therapeutic evaluation in a murine advanced atherosclerosis model showed that Thsd1 overexpression decreased plaque vulnerability by attenuating intraplaque vascular leakage, subsequently reducing macrophage accumulation and necrotic core size. Mechanistic studies in human endothelial cells demonstrated that THSD1 activates FAK-PI3K, leading to Rac1-mediated actin cytoskeleton regulation of adherens junctions and focal adhesion assembly. Conclusion: THSD1 is a new regulator of endothelial barrier function during vascular development and protects intraplaque microvessels against haemorrhaging in advanced atherosclerotic lesions

THSD1 preserves vascular integrity and protects against intraplaque haemorrhaging in ApoE(-/-) mice

AIMS: Impairment of the endothelial barrier leads to microvascular breakdown in cardiovascular disease and is involved in intraplaque haemorrhaging and the progression of advanced atherosclerotic lesions that are vulnerable to rupture. The exact mechanism that regulates vascular integrity requires further definition. Using a microarray screen for angiogenesis-associated genes during murine embryogenesis, we identified thrombospondin type I domain 1 (THSD1) as a new putative angiopotent factor with unknown biological function. We sought to characterize the role of THSD1 in endothelial cells during vascular development and cardiovascular disease. METHODS AND RESULTS: Functional knockdown of Thsd1 in zebrafish embryos and in a murine retina vascularization model induced severe haemorrhaging without affecting neovascular growth. In human carotid endarterectomy specimens, THSD1 expression by endothelial cells was detected in advanced atherosclerotic lesions with intraplaque haemorrhaging, but was absent in stable lesions, implying involvement of THSD1 in neovascular bleeding. In vitro, stimulation with pro-atherogenic factors (3% O2 and TNFα) decreased THSD1 expression in human endothelial cells, whereas stimulation with an anti-atherogenic factor (IL10) showed opposite effect. Therapeutic evaluation in a murine advanced atherosclerosis model showed that Thsd1 overexpression decreased plaque vulnerability by attenuating intraplaque vascular leakage, subsequently reducing macrophage accumulation and necrotic core size. Mechanistic studies in human endothelial cells demonstrated that THSD1 activates FAK-PI3K, leading to Rac1-mediated actin cytoskeleton regulation of adherens junctions and focal adhesion assembly. CONCLUSION: THSD1 is a new regulator of endothelial barrier function during vascular development and protects intraplaque microvessels against haemorrhaging in advanced atherosclerotic lesions