In Vivo Platelet Thrombus Formation in Microvessels of Spontaneously Hypertensive Rats

Lominadze, David; Joshua, Irving G.; Schuschke, Dale A.

doi:10.1016/s0895-7061(97)00214-8

Cited by 21 publications

(10 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…1,[4][5][6][7][8][9][10] Abnormalities in the functions of circulating immune cells which accompany the chronically elevated blood pressure associated with Ang-II 5,[7][8][9] and other models of HTN (e.g. high salt diet model 9,10 and the spontaneous HTN model 11,12 ) has been welldocumented. However, it is not the elevated blood pressure per se that is the driving factor for thrombosis, 9,13 but rather Ang-II itself.…”

Section: Introductionmentioning

confidence: 99%

Novel Role of T Cells and IL-6 (Interleukin-6) in Angiotensin II–Induced Microvascular Dysfunction

et al. 2019

View full text Add to dashboard Cite

Hypertension (HTN) is an established risk factor for subsequent cardiovascular diseases, with Angiotensin II (Ang-II) playing a major role in mediating thrombotic and inflammatory abnormalities. Although T cells and interleukin-6 (IL-6) play an important role in adaptive immune responses, little is known about their role(s) in the thrombo-inflammatory responses associated with Ang-II. Here we show using intravital microscopy coupled with the light/dye injury model that Rag-1 deficient (Rag-1 −/−) and IL-6 deficient (IL-6 −/−) mice are afforded protection against Ang-II induced thrombosis. Blocking IL-6 receptors (using CD126 and gp130 antibodies) significantly diminished Ang-II-mediated thrombosis and inflammatory cell recruitment in mice. Furthermore, the adoptive transfer of IL-6 −/−-derived T cells into Rag-1 −/− mice failed to accelerate Ang-II-induced thrombosis compared to Rag-1 −/− mice reconstituted with WT-derived T cells, suggesting T cell IL-6 mediates the thrombotic abnormalities associated Ang-II HTN. Interestingly, adoptive transfer of WT T cells into Rag-1 −/− /Ang-II mice resulted in increased numbers of immature platelets, which constitutes a more active platelet population i.e. pro-thrombotic and pro-inflammatory. To translate our in vivo findings, we used clinical samples to demonstrate that IL-6 also predisposes platelets to an interaction with collagen receptors, thereby increasing the propensity for platelets to aggregate and cause thrombosis. In summary, we provide compelling evidence for the involvement of IL-6, IL-6R and T cell-dependent IL-6 signaling in Ang-II induced thrombo-inflammation, which may provide new therapeutic possibilities for drug discovery programs for the management of HTN.

show abstract

Section: Introductionmentioning

confidence: 99%

Novel Role of T Cells and IL-6 (Interleukin-6) in Angiotensin II–Induced Microvascular Dysfunction

et al. 2019

View full text Add to dashboard Cite

show abstract

“…The pH of the bath was maintained by a constant supply of CO 2 gas, and the temperature was maintained at 35°C by a heating coil. The rat and the cremaster muscle preparation were positioned on a modified stage of a microscope (model MM-11, Nikon, Tokyo, Japan) so that the cremaster muscle, which is ϳ200 -250 m thick, could be observed by transmitted light or epi-illumination (22,23).…”

Section: Methodsmentioning

confidence: 99%

“…When JTE-013 or VPC 23019 was injected, S1P was injected via the cannula 10 min later. Before each experiment, autofluorescence of the observed area was recorded over a standard range of camera gains (22,23). FITC tagged to BSA (300 g/ml) was injected intra-arterially (0.2 ml/100 g body wt) and allowed to circulate for ϳ10 min.…”

Section: Methodsmentioning

confidence: 99%

Balance of S1P₁and S1P₂signaling regulates peripheral microvascular permeability in rat cremaster muscle vasculature

Lee

Gordon

Estrada

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

Lee JF, Gordon S, Estrada R, Wang L, Siow DL, Wattenberg BW, Lominadze D, Lee MJ. Balance of S1P 1 and S1P2 signaling regulates peripheral microvascular permeability in rat cremaster muscle vasculature. Am J Physiol Heart Circ Physiol 296: H33-H42, 2009. First published November 14, 2008 doi:10.1152/ajpheart.00097.2008.-Sphingosine-1-phosphate (S1P) regulates various molecular and cellular events in cultured endothelial cells, such as cytoskeletal restructuring, cell-extracellular matrix interactions, and intercellular junction interactions. We utilized the venular leakage model of the cremaster muscle vascular bed in Sprague-Dawley rats to investigate the role of S1P signaling in regulation of microvascular permeability. S1P signaling is mediated by the S1P family of G protein-coupled receptors (S1P 1-5 receptors). S1P1 and S1P2 receptors, which transduce stimulatory and inhibitory signaling, respectively, are expressed in the endothelium of the cremaster muscle vasculature. S1P administration alone via the carotid artery was unable to protect against histamineinduced venular leakage of the cremaster muscle vascular bed in Sprague-Dawley rats. However, activation of S1P 1-mediated signaling by SEW2871 and FTY720, two agonists of S1P 1, significantly inhibited histamine-induced microvascular leakage. Treatment with VPC 23019 to antagonize S1P 1-regulated signaling greatly potentiated histamine-induced venular leakage. After inhibition of S1P2 signaling by JTE-013, a specific antagonist of S1P2, S1P was able to protect microvascular permeability in vivo. Moreover, endothelial tight junctions and barrier function were regulated by S1P 1-and S1P 2-mediated signaling in a concerted manner in cultured endothelial cells. These data suggest that the balance between S1P 1 and S1P2 signaling regulates the homeostasis of microvascular permeability in the peripheral circulation and, thus, may affect total peripheral vascular resistance.spingosine-1-phosphate receptor subtypes; vascular integrity; signal transduction SPINGOSINE-1-PHOSPHATE (S1P), a serum-borne bioactive lipid mediator, regulates an array of biological activities in various cell types (13,14,28,42). Most, if not all, S1P-regulated functions are mediated by the S1P family of G protein-coupled receptors (1,20,48). Five members of the S1P receptor family have been identified: S1P 1 , S1P 2 , S1P 3 , S1P 4 , and S1P 5 , previously known as endothelial differentiation gene (EDG)-1, -5, -3, -6, and -8, respectively (6). It was demonstrated that S1P receptor subtypes couple to different G␣ polypeptides to regulate specific signaling pathways (2, 16, 46a). S1P receptor subtypes are expressed in distinct combinations in different cell types to produce an appropriate biological effect. For example, S1P 1 and S1P 3 are expressed in cultured endothelial cells (ECs) (18). The signaling pathways regulated by the S1P 1 and S1P 3 receptors in ECs are required for chemotaxis, adherens junction assembly, morphogenesis, and angiogenic response in vitro and in vivo (18 -20). H...

show abstract

“…A carotid artery cannula was used to continuously monitor mean arterial blood pressure (MABP) and heart rate with a transducer and a Micro-Med blood pressure analyzer (Louisville, KY). The right cremaster muscle was prepared for microvascular observations as described earlier (22).…”

Section: Methodsmentioning

confidence: 99%

Fibrinogen and fragment D-induced vascular constriction

Lominadze¹,

Tsakadze²,

Sen³

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

Elevated fibrinogen (Fg) concentration in blood is a high risk factor for many cardiovascular diseases. We hypothesize that Fg and its early degradation product, fragment D, may result in arterial constriction by binding endothelial intercellular adhesion molecule-1 (ICAM-1). The vasoconstriction induced by Fg and fragment D was studied in third-and second-order arterioles (3As and 2As, respectively) of Sprague-Dawley rat cremaster muscle in vivo, in aortic and femoral artery rings, and in the segments of first-order arterioles (1As) isolated from rat cremaster muscle. Intravascular infusion of Fg induced significant constriction of 3As and 2As (by 33.4 Ϯ 3.4 and 23.7 Ϯ 4.3%, respectively) in vivo and was abolished in the presence of the specific endothelin type A receptor blocker BQ-610. Fg and fragment D produced significant constriction of both aortic and femoral artery rings. (25), and stroke (9). Increased blood Fg concentration results in an increase in blood viscosity (20,23) and, therefore, an increase in blood flow shear stress (7). These in turn contribute to increased peripheral vascular resistance and lead to a reduction of blood flow in muscle, which exacerbates complications during hypertension (40). In addition, higher blood viscosity-induced increases in blood flow shear stress can activate endothelial cells (8, 38) and platelets (36). Endothelial cell activation results in expression of adhesion molecules, including intercellular adhesion molecule-1 (ICAM-1) (39). Fg is a ligand for ICAM-1 (18, 41), and as such, Fg binding to shear stressactivated platelets through platelet GPIIb/IIIa (34) may serve as a bridging mechanism for platelet adhesion to the endothelium (5). Therefore, elevated blood Fg content may lead to a higher predisposition for platelet thrombogenesis by triggering both platelet and endothelial activation mechanisms.Fg deposition onto the microvascular wall of mice after ischemia-reperfusion has been demonstrated elsewhere (26). This Fg deposition was partially reduced in an ICAM-1-mutant mouse, which suggests that Fg deposition at the vascular endothelium mainly occurs through endothelial ICAM-1. Hicks et al. (16) showed that Fg has a vasodilatory effect on the human saphenous vein. The authors suggested that this vasorelaxation could be a result of Fg binding to endothelial ICAM-1 and was induced by the expression of vasoactive mediators other than nitric oxide and prostacyclin.Various reports show the vasoactive effects of isolated peptides derived from plasmin digestion of fibrin and Fg in several vascular beds, including the lung (17), heart (27, 33), femoral artery (37), and mesenteric arteries (3). However, the mechanism of these effects still remains unclear. An attempt to study vasoconstriction of rat pulmonary artery rings induced by early digestion products of Fg failed to show any effect of these Fg fragments including fragment D (6). The effects of vascular constriction by Fg degradation products on the arterial rings were tested in the presence of 4 ϫ 10 Ϫ8 M phen...

show abstract

In Vivo Platelet Thrombus Formation in Microvessels of Spontaneously Hypertensive Rats

Cited by 21 publications

References 31 publications

Novel Role of T Cells and IL-6 (Interleukin-6) in Angiotensin II–Induced Microvascular Dysfunction

Novel Role of T Cells and IL-6 (Interleukin-6) in Angiotensin II–Induced Microvascular Dysfunction

Balance of S1P₁and S1P₂signaling regulates peripheral microvascular permeability in rat cremaster muscle vasculature

Fibrinogen and fragment D-induced vascular constriction

Contact Info

Product

Resources

About

In Vivo Platelet Thrombus Formation in Microvessels of Spontaneously Hypertensive Rats

Cited by 21 publications

References 31 publications

Novel Role of T Cells and IL-6 (Interleukin-6) in Angiotensin II–Induced Microvascular Dysfunction

Novel Role of T Cells and IL-6 (Interleukin-6) in Angiotensin II–Induced Microvascular Dysfunction

Balance of S1P1and S1P2signaling regulates peripheral microvascular permeability in rat cremaster muscle vasculature

Fibrinogen and fragment D-induced vascular constriction

Contact Info

Product

Resources

About

Balance of S1P₁and S1P₂signaling regulates peripheral microvascular permeability in rat cremaster muscle vasculature