198 research outputs found
Real-Time Maps of Fluid Flow Fields in Porous Biomaterials
Mechanical forces such as fluid shear have been shown to enhance cell growth
and differentiation, but knowledge of their mechanistic effect on cells is
limited because the local flow patterns and associated metrics are not
precisely known. Here we present real-time, noninvasive measures of local
hydrodynamics in 3D biomaterials based on nuclear magnetic resonance. Microflow
maps were further used to derive pressure, shear and fluid permeability fields.
Finally, remodeling of collagen gels in response to precise fluid flow
parameters was correlated with structural changes. It is anticipated that
accurate flow maps within 3D matrices will be a critical step towards
understanding cell behavior in response to controlled flow dynamics.Comment: 23 pages, 4 figure
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Angiopoietin-2 predicts morbidity in adults with Fontan physiology.
Morbidity in patients with single-ventricle Fontan circulation is common and includes arrhythmias, edema, and pulmonary arteriovenous malformations (PAVM) among others. We sought to identify biomarkers that may predict such complications. Twenty-five patients with Fontan physiology and 12 control patients with atrial septal defects (ASD) that underwent cardiac catheterization were included. Plasma was collected from the hepatic vein and superior vena cava and underwent protein profiling for a panel of 20 analytes involved in angiogenesis and endothelial dysfunction. Ten (40%) of Fontan patients had evidence of PAVM, eighteen (72%) had a history of arrhythmia, and five (20%) were actively in arrhythmia or had a recent arrhythmia. Angiopoietin-2 (Ang-2) was higher in Fontan patients (8,875.4 ± 3,336.9 pg/mL) versus the ASD group (1,663.6 ± 587.3 pg/mL, p < 0.0001). Ang-2 was higher in Fontan patients with active or recent arrhythmia (11,396.0 ± 3,457.7 vs 8,118.2 ± 2,795.1 pg/mL, p < 0.05). A threshold of 8,500 pg/mL gives Ang-2 a negative predictive value of 100% and positive predictive value of 42% in diagnosing recent arrhythmia. Ang-2 is elevated among adults with Fontan physiology. Ang-2 level is associated with active or recent arrhythmia, but was not found to be associated with PAVM
An essential requirement for β1 integrin in the assembly of extracellular matrix proteins within the vascular wall
Abstractβ1 integrin has been shown to contribute to vascular smooth muscle cell differentiation, adhesion and mechanosensation in vitro. Here we showed that deletion of β1 integrin at the onset of smooth muscle differentiation resulted in interrupted aortic arch, aneurysms and failure to assemble extracellular matrix proteins. These defects result in lethality prior to birth. Our data indicates that β1 integrin is not required for the acquisition, but it is essential for the maintenance of the smooth muscle cell phenotype, as levels of critical smooth muscle proteins are gradually reduced in mutant mice. Furthermore, while deposition of extracellular matrix was not affected, its structure was disrupted. Interestingly, defects in extracellular matrix and vascular wall assembly, were restricted to the aortic arch and its branches, compromising the brachiocephalic and carotid arteries and to the exclusion of the descending aorta. Additional analysis of β1 integrin in the pharyngeal arch smooth muscle progenitors was performed using wnt1Cre. Neural crest cells deleted for β1 integrin were able to migrate to the pharyngeal arches and associate with endothelial lined arteries; but exhibited vascular remodeling defects and early lethality. This work demonstrates that β1 integrin is dispensable for migration and initiation of the smooth muscle differentiation program, however, it is essential for remodeling of the pharyngeal arch arteries and for the assembly of the vessel wall of their derivatives. It further establishes a critical role of β1 integrin in the protection against aneurysms that is particularly confined to the ascending aorta and its branches
Vav3-induced cytoskeletal dynamics contribute to heterotypic properties of endothelial barriers
[EN]Through multiple cell-cell and cell-matrix interactions, epithelial and endothelial sheets form tight barriers. Modulators of the cytoskeleton contribute to barrier stability and act as rheostats of vascular permeability. In this study, we sought to identify cytoskeletal regulators that underlie barrier diversity across vessels. To achieve this, we correlated functional and structural barrier features to gene expression of endothelial cells (ECs) derived from different vascular beds. Within a subset of identified candidates, we found that the guanosine nucleotide exchange factor Vav3 was exclusively expressed by microvascular ECs and was closely associated with a high-resistance barrier phenotype. Ectopic expression of Vav3 in large artery and brain ECs significantly enhanced barrier resistance and cortical rearrangement of the actin cytoskeleton. Mechanistically, we found that the barrier effect of Vav3 is dependent on its Dbl homology domain and downstream activation of Rap1. Importantly, inactivation of Vav3 in vivo resulted in increased vascular leakage, highlighting its function as a key regulator of barrier stability. © 2018 Hilfenhaus et al
GKAP Acts as a Genetic Modulator of NMDAR Signaling to Govern Invasive Tumor Growth.
Genetic linkage analysis previously suggested that GKAP, a scaffold protein of the N-methyl-D-aspartate receptor (NMDAR), was a potential modifier of invasion in a mouse model of pancreatic neuroendocrine tumor (PanNET). Here, we establish that GKAP governs invasive growth and treatment response to NMDARÂ inhibitors of PanNET via its pivotal role in regulating NMDAR pathway activity. Combining genetic knockdown of GKAP and pharmacological inhibition of NMDAR, we implicate as downstream effectors FMRP and HSF1, which along with GKAP demonstrably support invasiveness of PanNET and pancreatic ductal adenocarcinoma cancer cells. Furthermore, we distilled genome-wide expression profiles orchestrated by the NMDAR-GKAP signaling axis, identifying transcriptome signatures in tumors with low/inhibited NMDAR activity that significantly associate with favorable patient prognosis in several cancer types
Endothelial deletion of murine Jag1 leads to valve calcification and congenital heart defects associated with Alagille syndrome
The Notch signaling pathway is an important contributor to the development and homeostasis of the cardiovascular system. Not surprisingly, mutations in Notch receptors and ligands have been linked to a variety of hereditary diseases that impact both the heart and the vasculature. In particular, mutations in the gene encoding the human Notch ligand jagged 1 result in a multisystem autosomal dominant disorder called Alagille syndrome, which includes tetralogy of Fallot among its more severe cardiac pathologies. Jagged 1 is expressed throughout the developing embryo, particularly in endothelial cells. Here, we demonstrate that endothelial-specific deletion of Jag1 leads to cardiovascular defects in both embryonic and adult mice that are reminiscent of those in Alagille syndrome. Mutant mice display right ventricular hypertrophy, overriding aorta, ventricular septal defects, coronary vessel abnormalities and valve defects. Examination of mid-gestational embryos revealed that the loss of Jag1, similar to the loss of Notch1, disrupts endothelial-to-mesenchymal transition during endocardial cushion formation. Furthermore, adult mutant mice exhibit cardiac valve calcifications associated with abnormal matrix remodeling and induction of bone morphogenesis. This work shows that the endothelium is responsible for the wide spectrum of cardiac phenotypes displayed in Alagille Syndrome and it demonstrates a crucial role for Jag1 in valve morphogenesis
Incongruence between transcriptional and vascular pathophysiological cell states
Research in R.B.’s laboratory was supported by the European Research
Council Starting Grant AngioGenesHD (638028) and Consolidator
Grant AngioUnrestUHD (101001814), the CNIC Intramural Grant
Program Severo Ochoa (11-2016-IGP-SEV-2015-0505), the Ministerio
de Ciencia e Innovación (MCIN) (SAF2013-44329-P, RYC-2013-
13209, and SAF2017-89299-P) and ‘La Caixa’ Banking Foundation
(HR19-00120). J.V.’s laboratory was supported by MCIN (PGC2018-
097019-B-I00 and PID2021-122348NB-I00) and La Caixa (HR17-00247
and HR22-00253). K.G.’s laboratory was supported by Knut and
Alice Wallenberg Foundation (2020.0057) and Vetenskapsrådet
(2021-04896). The CNIC is supported by Instituto de Salud Carlos
III, MCIN, and the Pro CNIC Foundation, and is a Severo Ochoa
Center of Excellence (grant CEX2020-001041-S funded by MCIN/
AEI/10.13039/501100011033). Microscopy experiments were
performed at the Microscopy and Dynamic Imaging Unit, CNIC,
ICTS-ReDib, co-funded by MCIN/AEI/10.13039/501100011033 and
FEDER ‘Una manera de hacer Europa’ (ICTS-2018-04-CNIC-16). M.F.-C.
was supported by PhD fellowships from La Caixa (CX_E-2015-01)
and Boehringer Ingelheim travel grants. S.M. was supported by the
Austrian Science Fund (J4358). A.R. was supported by the Youth
Employment Initiative (PEJD-2019-PRE/BMD-16990). L.G.-O. was
supported by the Spanish Ministry of Economy and Competitiveness
(PRE2018-085283). We thank S. Bartlett (CNIC) for English editing,
as well as the members of the Transgenesis, Microscopy, Genomics,
Citometry and Bioinformatic units at CNIC. We also thank F. Radtke
(Swiss Institute for Experimental Cancer Research), R. H. Adams (Max
Planck Institute for Molecular Biomedicine), F. Alt (Boston Children’s
Hospital, Harvard Medical School), T. Honjo (Kyoto University Institute
for Advanced Studies), I. Flores (CNIC), J. Lewis (Cancer Research
UK London Research Institute), S. Habu (Tokai University School of
Medicine), T. Gridley (Maine Health Institute for Research) and C.
Brakebusch (Biotech Research and Innovation Centre) for sharing the
Dll4floxed, Notch1floxed, Notch2floxed, Cdh5(PAC)-creERT2, Myc floxed,
Rbpj floxed, p21−/−, Jag1floxed, Dll1floxed, Jag2floxed and Rac1floxed mice.S
Perspectives on Cognitive Phenotypes and Models of Vascular Disease
Clinical investigations have established that vascular-Associated medical conditions are significant risk factors for various kinds of dementia. And yet, we are unable to associate certain types of vascular deficiencies with specific cognitive impairments. The reasons for this are many, not the least of which are that most vascular disorders are multi-factorial and the development of vascular dementia in humans is often a multi-year or multi-decade progression. To better study vascular disease and its underlying causes, the National Heart, Lung, and Blood Institute of the National Institutes of Health has invested considerable resources in the development of animal models that recapitulate various aspects of human vascular disease. Many of these models, mainly in the mouse, are based on genetic mutations, frequently using single-gene mutations to examine the role of specific proteins in vascular function. These models could serve as useful tools for understanding the association of specific vascular signaling pathways with specific neurological and cognitive impairments related to dementia. To advance the state of the vascular dementia field and improve the information sharing between the vascular biology and neurobehavioral research communities, National Heart, Lung, and Blood Institute convened a workshop to bring in scientists from these knowledge domains to discuss the potential utility of establishing a comprehensive phenotypic cognitive assessment of a selected set of existing mouse models, representative of the spectrum of vascular disorders, with particular attention focused on age, sex, and rigor and reproducibility. The workshop highlighted the potential of associating well-characterized vascular disease models, with validated cognitive outcomes, that can be used to link specific vascular signaling pathways with specific cognitive and neurobehavioral deficits
Anchorage of VEGF to the extracellular matrix conveys differential signaling responses to endothelial cells
Matrix-bound VEGF elicits more distinct vascular effects than soluble VEGF, including prolonged VEGFR2 activation with altered patterns of tyrosine activation and downstream enhancement of the p38/MAPK pathway
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