Reciprocal stabilization of coagulation factor XIII-A and -B subunits is a determinant of plasma FXIII concentration.

Transglutaminase factor XIII (FXIII) is essential for hemostasis, wound healing, and pregnancy maintenance. Plasma FXIII is composed of A and B subunit dimers synthesized in cells of hematopoietic origin and hepatocytes, respectively. The subunits associate tightly in circulation as FXIII-A2B2.

Comparing Focused-Tracked and Plane Wave-Tracked ARFI Log(VoA) In Silico and in Application to Human Carotid Atherosclerotic Plaque, Ex Vivo.

A significant risk factor for ischemic stroke is carotid atherosclerotic plaque that is susceptible to rupture, with rupture potential conveyed by plaque morphology. Human carotid plaque composition and structure have been delineated noninvasively and in vivo by evaluating log(VoA), a parameter derived as the decadic log of the second time derivative of displacement induced by an acoustic radiation force impulse (ARFI). In prior work, ARFI-induced displacement was measured using conventional focused tracking; however, this requires a long data acquisition period, thereby reducing framerate.

Insulin Elevates ID2 Expression in Trophoblasts and Aggravates Preeclampsia in Obese ASB4-Null Mice.

Obesity is a risk factor for preeclampsia. We investigated how obesity influences preeclampsia in mice lacking ankyrin-repeat-and-SOCS-box-containing-protein 4 (ASB4), which promotes trophoblast differentiation via degrading the inhibitor of DNA-binding protein 2 (ID2). mice on normal chow (NC) develop mild preeclampsia-like phenotypes during pregnancy, including hypertension, proteinuria, and reduced litter size.

Carotid Plaque Fibrous Cap Thickness Measurement by ARFI Variance of Acceleration: In Vivo Human Results.

This study evaluates the performance of an acoustic radiation force impulse (ARFI)-based outcome parameter, the decadic logarithm of the variance of acceleration, or log(VoA), for measuring carotid fibrous cap thickness. Carotid plaque fibrous cap thickness measurement by log(VoA) was compared to that by ARFI peak displacement (PD) in patients undergoing clinically indicated carotid endarterectomy using a spatially-matched histological validation standard. Fibrous caps in parametric log(VoA) and PD images were automatically segmented using a custom clustering algorithm, and a pathologist with expertise in atherosclerosis hand-delineated fibrous caps in histology.

Rivaroxaban does not affect growth of human pancreatic tumors in mice.

Background: Some clinical studies have shown that low-molecular-weight heparins (LMWHs) prolong the survival of cancer patients. In addition, various anticoagulants have been shown to reduce growth of tumors in mice. However, there are no studies on the effect of the factor Xa inhibitor rivaroxaban on growth of human pancreatic tumors in nude mice.

Delineation of Human Carotid Plaque Features In Vivo by Exploiting Displacement Variance.

While in vivo acoustic radiation force impulse (ARFI)-induced peak displacement (PD) has been demonstrated to have high sensitivity and specificity for differentiating soft from stiff plaque components in patients with carotid plaque, the parameter exhibits poorer performance for distinguishing between plaque features with similar stiffness. To improve discrimination of carotid plaque features relative to PD, we hypothesize that signal correlation and signal-to-noise ratio (SNR) can be combined, outright or via displacement variance. Plaque feature detection by displacement variance, evaluated as the decadic logarithm of the variance of acceleration and termed "log(VoA)," was compared to that achieved by exploiting SNR, cross correlation coefficient, and ARFI-induced PD outcome metrics.

ARFI variance of acceleration (VoA) for noninvasive characterization of human carotid plaques in vivo.

Rather than degree of stenosis, assessing plaque structure and composition is relevant to discerning risk for plaque rupture with downstream ischemic event. The structure and composition of carotid plaque has been assessed noninvasively using Acoustic Radiation Force Impulse (ARFI) ultrasound imaging. In particular, ARFI-derived peak displacement (PD) estimations have been demonstrated for discriminating soft (lipid rich necrotic core (LRNC) or intraplaque hemorrhage (IPH)) from stiff (collagen (COL) or calcium (CAL)) plaque features; however, PD did not differentiate LRNC from IPH or COL from CAL.

Performance of acoustic radiation force impulse ultrasound imaging for carotid plaque characterization with histologic validation.

Objective: Stroke is commonly caused by thromboembolic events originating from ruptured carotid plaque with vulnerable composition. This study assessed the performance of acoustic radiation force impulse (ARFI) imaging, a noninvasive ultrasound elasticity imaging method, for delineating the composition of human carotid plaque in vivo with histologic validation.

Methods: Carotid ARFI images were captured before surgery in 25 patients undergoing clinically indicated carotid endarterectomy.

Non-invasive in vivo characterization of human carotid plaques with acoustic radiation force impulse ultrasound: comparison with histology after endarterectomy.

Ischemic stroke from thromboembolic sources is linked to carotid artery atherosclerotic disease with a trend toward medical management in asymptomatic patients. Extent of disease is currently diagnosed by non-invasive imaging techniques that measure luminal stenosis, but it has been suggested that a better biomarker for determining risk of future thromboembolic events is plaque morphology and composition. Specifically, plaques that are composed of mechanically soft lipid/necrotic regions covered by thin fibrous caps are the most vulnerable to rupture.

Acoustic radiation force beam sequence performance for detection and material characterization of atherosclerotic plaques: preclinical, ex vivo results.

This work presents preclinical data demonstrating performance of acoustic radiation force (ARF)-based elasticity imaging with five different beam sequences for atherosclerotic plaque detection and material characterization. Twelve trained, blinded readers evaluated parametric images taken ex vivo under simulated in vivo conditions of 22 porcine femoral arterial segments. Receiver operating characteristic (ROC) curve analysis was carried out to quantify reader performance using spatially-matched immunohistochemistry for validation.

α(1,3)-Fucosyltransferases FUT4 and FUT7 control murine susceptibility to thrombosis.

The α(1,3)-fucosyltransferases, types IV and VII (FUT4 and FUT7, respectively), are required for the synthesis of functional selectin-type leukocyte adhesion molecule ligands. The selectins and their ligands modulate leukocyte trafficking, and P-selectin and its ligand, P-selectin glycoprotein ligand-1, can modulate hemostasis and thrombosis. Regulation of thrombosis by FUT4 and/or FUT7 activity was examined in mouse models of carotid artery thrombosis and collagen/epinephrine-induced thromboembolism.

Rib fractures and death from deletion of osteoblast βcatenin in adult mice is rescued by corticosteroids.

Ribs are primarily made of cortical bone and are necessary for chest expansion and ventilation. Rib fractures represent the most common type of non-traumatic fractures in the elderly yet few studies have focused on the biology of rib fragility. Here, we show that deletion of βcatenin in Col1a2 expressing osteoblasts of adult mice leads to aggressive osteoclastogenesis with increased serum levels of the osteoclastogenic cytokine RANKL, extensive rib resorption, multiple spontaneous rib fractures and chest wall deformities.

Bmper inhibits endothelial expression of inflammatory adhesion molecules and protects against atherosclerosis.

Objective: Bone morphogenetic proteins (Bmps) are important mediators of inflammation and atherosclerosis, though their mechanism of action is not fully understood. To better understand the contribution of the Bmp signaling pathway in vascular inflammation, we investigated the role of Bmper (Bmp endothelial cell precursor-derived regulator), an extracellular Bmp modulator, in an induced in vivo model of inflammation and atherosclerosis.

Methods And Results: We crossed apolipoprotein E-deficient (ApoE(-/-)) mice with mice missing 1 allele of Bmper (Bmper(+/-) mice used in the place of Bmper(-/-) mice that die at birth) and measured the development of atherosclerosis in mice fed a high-fat diet.

Functional redundancy of SWI/SNF catalytic subunits in maintaining vascular endothelial cells in the adult heart.

Rationale: Mating type switching/sucrose non-fermenting (SWI/SNF) chromatin-remodeling complexes utilize either BRG1 or BRM as a catalytic subunit to alter nucleosome position and regulate gene expression. BRG1 is required for vascular endothelial cell (VEC) development and embryonic survival, whereas BRM is dispensable.

Objective: To circumvent embryonic lethality and study Brg1 function in adult tissues, we used conditional gene targeting.

Anaplasma phagocytophilum infects mast cells via alpha1,3-fucosylated but not sialylated glycans and inhibits IgE-mediated cytokine production and histamine release.

Mast cells are sentinels for infection. Upon exposure to pathogens, they release their stores of proinflammatory cytokines, chemokines, and histamine. Mast cells are also important for the control of certain tick-borne infections.

Sent to destroy: the ubiquitin proteasome system regulates cell signaling and protein quality control in cardiovascular development and disease.

The ubiquitin proteasome system (UPS) plays a crucial role in biological processes integral to the development of the cardiovascular system and cardiovascular diseases. The UPS prototypically recognizes specific protein substrates and places polyubiquitin chains on them for subsequent destruction by the proteasome. This system is in place to degrade not only misfolded and damaged proteins, but is essential also in regulating a host of cell signaling pathways involved in proliferation, adaptation to stress, regulation of cell size, and cell death.

Disruption of tissue-specific fucosyltransferase VII, an enzyme necessary for selectin ligand synthesis, suppresses atherosclerosis in mice.

A hallmark feature of atherosclerosis is that circulating mononuclear cells adhere to the endothelium and migrate into the subendothelial space. This adhesion is mediated by molecules such as selectins that are expressed on the surfaces of both leukocytes and endothelial cells. In this study, we have determined the role of tissue-specific fucosyltransferase VII (FucT-VII), an enzyme necessary for selectin ligand synthesis, in the development of atherosclerosis.

A role for leukocyte-endothelial adhesion mechanisms in epilepsy.

The mechanisms involved in the pathogenesis of epilepsy, a chronic neurological disorder that affects approximately one percent of the world population, are not well understood. Using a mouse model of epilepsy, we show that seizures induce elevated expression of vascular cell adhesion molecules and enhanced leukocyte rolling and arrest in brain vessels mediated by the leukocyte mucin P-selectin glycoprotein ligand-1 (PSGL-1, encoded by Selplg) and leukocyte integrins alpha(4)beta(1) and alpha(L)beta(2). Inhibition of leukocyte-vascular interactions, either with blocking antibodies or by genetically interfering with PSGL-1 function in mice, markedly reduced seizures.

Mice with heterozygous deficiency of lipoic acid synthase have an increased sensitivity to lipopolysaccharide-induced tissue injury.

Alpha-lipoic acid (1, 2-dithiolane-3-pentanoic acid; LA), synthesized in mitochondria by LA synthase (Lias), is a potent antioxidant and a cofactor for metabolic enzyme complexes. In this study, we examined the effect of genetic reduction of LA synthesis on its antioxidant and anti-inflammatory properties using a model of LPS-induced inflammation in Lias+/- mice. The increase of plasma proinflammatory cytokine, TNF-alpha, and NF-kappaB at an early phase following LPS injection was greater in Lias+/- mice compared with Lias+/+ mice.

Genetics of atherosclerosis in murine models.

The pathology of atherosclerotic lesions that develop in mouse models of atherosclerosis, such as those lacking apolipoprotein E or lacking the low density lipoprotein receptor, is very similar to that seen in human patients. Consequently, genetic approaches to studying atherosclerosis in these mouse models have produced a wealth of information relevant to the genetic factors and pathways that modify the early stages of atherosclerosis in humans. Despite these advances, the later stages of atherosclerosis in humans, including spontaneous plaque rupture and hemorrhage, have not been observed reliably in current mouse models.

Conditional deletion of focal adhesion kinase leads to defects in ventricular septation and outflow tract alignment.

To examine a role for focal adhesion kinase (FAK) in cardiac morphogenesis, we generated a line of mice with a conditional deletion of FAK in nkx2-5-expressing cells (herein termed FAKnk mice). FAKnk mice died shortly after birth, likely resulting from a profound subaortic ventricular septal defect and associated malalignment of the outflow tract. Additional less penetrant phenotypes included persistent truncus arteriosus and thickened valve leaflets.

Alpha-galactosidase A deficiency leads to increased tissue fibrin deposition and thrombosis in mice homozygous for the factor V Leiden mutation.

Background: Factor V Leiden (FVL) is a common genetic risk factor for vascular thrombosis in humans. Fabry disease, an X-linked lysosomal storage disorder attributable to alpha-galactosidase A (GLA) deficiency, is associated with premature vascular events that may be thrombotic in nature.

Methods: To examine a potential interaction between FvL and Gla deficiency in vivo, we analyzed tissue fibrin deposition in mice carrying combined mutations in FvL and Gla.

Bradykinin B2 receptor knockout mice are protected from thrombosis by increased nitric oxide and prostacyclin.

Bradykinin (BK) liberates nitric oxide, prostacyclin, and tissue plasminogen activator from endothelial cells. We hypothesized that BK B2 receptor knockout (KO) mice (BKB2R(-/-)) have increased thrombosis risk. Paradoxically, the BKB2R(-/-) mice have long bleeding times and delayed carotid artery thrombosis, 78 +/- 6.

Shigatoxin triggers thrombotic thrombocytopenic purpura in genetically susceptible ADAMTS13-deficient mice.

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening illness caused by deficiency of the vWF-cleaving protease ADAMTS13. Here we show that ADAMTS13-deficient mice are viable and exhibit normal survival, although vWF-mediated platelet-endothelial interactions are significantly prolonged. Introduction of the genetic background CASA/Rk (a mouse strain with elevated plasma vWF) resulted in the appearance of spontaneous thrombocytopenia in a subset of ADAMTS13-deficient mice and significantly decreased survival.