scholarly journals Requirement of β1 integrin for endothelium-dependent vasodilation and collateral formation in hindlimb ischemia

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Carina Henning ◽  
Anna Branopolski ◽  
Dominik Schuler ◽  
Dimitrios Dimitroulis ◽  
Patrik Huelsemann ◽  
...  
Keyword(s):  
Blood Flow ◽  
Endothelial Cell ◽  
Femoral Artery ◽  
Β1 Integrin ◽  
Hindlimb Ischemia ◽  
High Frequency Ultrasound ◽  
Blocking Antibody ◽  
Arterial Lumen ◽  
Collateral Arteries ◽  
Acute Increase

AbstractAn acute increase in blood flow triggers flow-mediated dilation (FMD), which is mainly mediated by endothelial nitric oxide synthase (eNOS). A long-term increase in blood flow chronically enlarges the arterial lumen, a process called arteriogenesis. In several common human diseases, these processes are disrupted for as yet unknown reasons. Here, we asked whether β1 integrin, a mechanosensory protein in endothelial cells, is required for FMD and arteriogenesis in the ischemic hindlimb. Permanent ligation of the femoral artery in C57BL/6 J mice enlarged pre-existing collateral arteries and increased numbers of arterioles in the thigh. In the lower leg, the numbers of capillaries increased. Notably, injection of β1 integrin-blocking antibody or tamoxifen-induced endothelial cell-specific deletion of the gene for β1 integrin (Itgb1) inhibited both arteriogenesis and angiogenesis. Using high frequency ultrasound, we demonstrated that β1 integrin-blocking antibody or endothelial cell-specific depletion of β1 integrin attenuated FMD of the femoral artery, and blocking of β1 integrin function did not further decrease FMD in eNOS-deficient mice. Our data suggest that endothelial β1 integrin is required for both acute and chronic widening of the arterial lumen in response to hindlimb ischemia, potentially via functional interaction with eNOS.

Computational Fluid Dynamics Analysis of Blood Flow Through Stented Arteries

2013 ◽  
Author(s):  
Shafiullah Mohammad ◽  
Pradip Majumdar
Keyword(s):  
Blood Flow ◽  
Femoral Artery ◽  
Cardiac Cycle ◽  
Stokes Equations ◽  
Interventional Procedure ◽  
Wall Thickening ◽  
Velocity Waveform ◽  
Arterial Lumen ◽  
Computational Fluid Dynamics Analysis ◽  
Intravascular Stents

Atherosclerosis is a vascular disease that reduces arterial lumen size through plaque deposition and arterial wall thickening. The pathological complications of atherosclerosis, namely heart disease and stroke, remain the leading cause of mortality in the world. The most common interventional procedure against atherosclerosis involves the placement of an intravascular stent. Intravascular stents are small tube like structures placed into Stenotic arteries to restore the blood flow. In this study CFD analysis is performed on the femoral artery by considering blood flow as a pulsating, incompressible and Newtonian flow over a realistic velocity waveform of the femoral artery. The artery is considered as a rigid and straight with a branch. The governing transient Navier-Stokes equations are solved using commercial software code Star-CCM+. Simulations are performed on healthy, atherosclerosis affected and Stented femoral arteries. Velocity and wall shear stress fields over the cardiac cycle are analyzed to predict the outcome of the interventions in terms of recirculation and stagnation regions and identify improved stent designs. The flow patterns in the arteries are highly modulating along with the cardiac cycle and a strong function of the waveform created by the heartbeat. The complex blood flow pattern with slow moving regions, flow separation and recirculatory form near the wall during cardiac cycle is the major contributing factor to the formation of the atherosclerotic plaque at that location. It was demonstrated that adverse flow field created upstream and downstream of the blockage may cause enhanced growth in size of the blockage. The stent design also plays significant role in the possibility of restenosis.

Increased vascular resistance during complement-activated plasma infusion in swine

1987 ◽  
Vol 253 (1) ◽  
pp. H58-H65
Author(s):  
L. J. Swenson ◽  
G. A. Pantely ◽  
C. G. Anselone ◽  
J. D. Bristow
Keyword(s):  
Blood Flow ◽  
Vascular Resistance ◽  
Femoral Artery ◽  
Femoral Vein ◽  
Adrenergic Blockade ◽  
Plasma Infusion ◽  
Artery Pressure ◽  
Femoral Artery Blood Flow ◽  
Acute Increase ◽  
Control Infusion

To investigate the acute effects of complement activation on blood flow, we infused complement-activated plasma into the femoral artery of the isolated hindlimb of 19 anesthetized swine. Femoral artery blood flow decreased abruptly, was lowest at 1 min of the infusion, and thereafter slowly increased despite continued infusion. There was no significant change in femoral artery pressure or femoral vein pressure, confirming an acute increase in vascular resistance. Control infusion of heat-decomplemented-activated plasma caused no change in pressure or flow. Slope of the femoral artery pressure-flow relationship during maximal vasodilation with adenosine was significantly lower after infusion of complement-activated plasma, confirming a persistent increase in vascular resistance. Neither the acute nor the persistent increase in vascular resistance was prevented by alpha-adrenergic blockade with phentolamine or granulocytopenia produced by cyclophosphamide. We conclude that complement-activated plasma infusion in the femoral circulation causes an abrupt increase in vascular resistance that persists during pharmacologically maximal vasodilation, is not due to alpha-mediated vasoconstriction, and is not altered by severe granulocytopenia.

scholarly journals The Lipopeptide MALP-2 Promotes Collateral Growth

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 997
Author(s):  
Kerstin Troidl ◽  
Christian Schubert ◽  
Ann-Kathrin Vlacil ◽  
Ramesh Chennupati ◽  
Sören Koch ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Femoral Artery ◽  
Hind Limb ◽  
Immune Defense ◽  
Laser Speckle ◽  
Mesenteric Arteries ◽  
Endothelial Cell Proliferation ◽  
Collateral Arteries ◽  
Collateral Growth

Beyond their role in pathogen recognition and the initiation of immune defense, Toll-like receptors (TLRs) are known to be involved in various vascular processes in health and disease. We investigated the potential of the lipopeptide and TLR2/6 ligand macrophage activating protein of 2-kDA (MALP-2) to promote blood flow recovery in mice. Hypercholesterolemic apolipoprotein E (Apoe)-deficient mice were subjected to microsurgical ligation of the femoral artery. MALP-2 significantly improved blood flow recovery at early time points (three and seven days), as assessed by repeated laser speckle imaging, and increased the growth of pre-existing collateral arteries in the upper hind limb, along with intimal endothelial cell proliferation in the collateral wall and pericollateral macrophage accumulation. In addition, MALP-2 increased capillary density in the lower hind limb. MALP-2 enhanced endothelial nitric oxide synthase (eNOS) phosphorylation and nitric oxide (NO) release from endothelial cells and improved the experimental vasorelaxation of mesenteric arteries ex vivo. In vitro, MALP-2 led to the up-regulated expression of major endothelial adhesion molecules as well as their leukocyte integrin receptors and consequently enhanced the endothelial adhesion of leukocytes. Using the experimental approach of femoral artery ligation (FAL), we achieved promising results with MALP-2 to promote peripheral blood flow recovery by collateral artery growth.

Subcutaneous and transcutaneous monitoring of murine hindlimb ischemia byin vivoRaman spectroscopy

The Analyst ◽  
2019 ◽  
Vol 144 (15) ◽  
pp. 4677-4686
Author(s):  
Rida Al-Rifai ◽  
Claire Tournois ◽  
Samar Kheirallah ◽  
Nicole Bouland ◽  
Gaël Poitevin ◽  
...  
Keyword(s):  
Raman Spectroscopy ◽  
Blood Flow ◽  
Femoral Artery ◽  
Flow Analysis ◽  
Functional Tests ◽  
Hindlimb Ischemia ◽  
Artery Ligation ◽  
Transcutaneous Monitoring ◽  
Blood Flow Analysis

We have investigated the development of murine hindlimb ischemia from day 1 to day 55 after femoral artery ligation (FAL) using blood flow analysis, functional tests, histopathological staining, andin vivoRaman spectroscopy.

scholarly journals Ischemic-Trained Monocytes Improve Arteriogenesis in a Mouse Model of Hindlimb Ischemia

2021 ◽  
Author(s):  
Gustavo Falero-Diaz ◽  
Catarina de A. Barboza ◽  
Felipe Pires ◽  
Maeva Fanchin ◽  
Jingjing Ling ◽  
...  
Keyword(s):  
Blood Flow ◽  
Femoral Artery ◽  
Cholesterol Metabolism ◽  
Hypoxia Inducible Factor ◽  
Artery Occlusion ◽  
Immunologic Memory ◽  
Hindlimb Ischemia ◽  
Gene Profile ◽  
Glut 1 ◽  
Femoral Artery Occlusion

Objective: Monocytes, which play an important role in arteriogenesis, can build immunologic memory by a functional reprogramming that modifies their response to a second challenge. This process, called trained immunity, is evoked by insults that shift monocyte metabolism, increasing HIF (hypoxia-inducible factor)-1α levels. Since ischemia enhances HIF-1α, we evaluate whether ischemia can lead to a functional reprogramming of monocytes, which would contribute to arteriogenesis after hindlimb ischemia. Methods and Results: Mice exposed to ischemia by 24 hours of femoral artery occlusion (24 hours trained) or sham were subjected to hindlimb ischemia one week later; the 24-hour trained mice showed significant improvement in blood flow recovery and arteriogenesis after hindlimb ischemia. Adoptive transfer using bone marrow-derived monocytes (BM-Mono) from 24-hour trained or sham donor mice, demonstrated that recipients subjected to hindlimb ischemia who received 24 hours ischemic-trained monocytes had remarkable blood flow recovery and arteriogenesis. Further, ischemic-trained BM-Mono had increased HIF-1α and GLUT-1 gene expression during femoral artery occlusion. Circulating cytokines and GLUT-1 were also upregulated during femoral artery occlusion.Transcriptomic analysis and confirmatory qPCR performed in 24 hours trained and sham BM-Mono revealed that among the 15 top differentially expressed genes, 4 were involved in lipid metabolism in the ischemic-trained monocytes. Lipidomic analysis confirmed that ischemia training altered the cholesterol metabolism of these monocytes. Further, several histone-modifying epigenetic enzymes measured by qPCR were altered in mouse BM-Mono exposed to 24 hours hypoxia. Conclusions: Ischemia training in BM-Mono leads to a unique gene profile and improves blood flow and arteriogenesis after hindlimb ischemia.

scholarly journals Age-Dependent Dysregulation of Muscle Vasculature and Blood Flow Recovery after Hindlimb Ischemia in the mdx Model of Duchenne Muscular Dystrophy

Biomedicines ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 481
Author(s):  
Paulina Podkalicka ◽  
Olga Mucha ◽  
Katarzyna Kaziród ◽  
Iwona Bronisz-Budzyńska ◽  
Sophie Ostrowska-Paton ◽  
...  
Keyword(s):  
Blood Flow ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Blood Vessels ◽  
Mdx Mice ◽  
Hindlimb Ischemia ◽  
Double Positive ◽  
Functional Studies ◽  
Age Dependent ◽  
Dystrophic Mice

Duchenne muscular dystrophy (DMD), caused by a lack of functional dystrophin, is characterized by progressive muscle degeneration. Interestingly, dystrophin is also expressed in endothelial cells (ECs), and insufficient angiogenesis has already been hypothesized to contribute to DMD pathology, however, its status in mdx mice, a model of DMD, is still not fully clear. Our study aimed to reveal angiogenesis-related alterations in skeletal muscles of mdx mice compared to wild-type (WT) counterparts. By investigating 6- and 12-week-old mice, we sought to verify if those changes are age-dependent. We utilized a broad spectrum of methods ranging from gene expression analysis, flow cytometry, and immunofluorescence imaging to determine the level of angiogenic markers and to assess muscle blood vessel abundance. Finally, we implemented the hindlimb ischemia (HLI) model, more biologically relevant in the context of functional studies evaluating angiogenesis/arteriogenesis processes. We demonstrated that both 6- and 12-week-old dystrophic mice exhibited dysregulation of several angiogenic factors, including decreased vascular endothelial growth factor A (VEGF) in different muscle types. Nonetheless, in younger, 6-week-old mdx animals, neither the abundance of CD31+α-SMA+ double-positive blood vessels nor basal blood flow and its restoration after HLI was affected. In 12-week-old mdx mice, although a higher number of CD31+α-SMA+ double-positive blood vessels and an increased percentage of skeletal muscle ECs were found, the abundance of pericytes was diminished, and blood flow was reduced. Moreover, impeded perfusion recovery after HLI associated with a blunted inflammatory and regenerative response was evident in 12-week-old dystrophic mice. Hence, our results reinforce the hypothesis of age-dependent angiogenic dysfunction in dystrophic mice. In conclusion, we suggest that older mdx mice constitute an appropriate model for preclinical studies evaluating the effectiveness of vascular-based therapies aimed at the restoration of functional angiogenesis to mitigate DMD severity.

scholarly journals Pak1 regulates branching morphogenesis in 3D MDCK cell culture by a PIX and β1-integrin-dependent mechanism

2010 ◽  
Vol 299 (1) ◽  
pp. C21-C32 ◽  
Author(s):  
Michael P. Hunter ◽  
Mirjam M. Zegers
Keyword(s):  
Cell Culture ◽  
Mdck Cell ◽  
Three Dimensional ◽  
3D Culture ◽  
Branching Morphogenesis ◽  
Dominant Negative ◽  
Β1 Integrin ◽  
Blocking Antibody ◽  
Important Regulator ◽  
P21 Activated Kinase

Branching morphogenesis is a fundamental process in the development of the kidney. This process gives rise to a network of ducts, which form the collecting system. Defective branching can lead to a multitude of kidney disorders including agenesis and reduced nephron number. The formation of branching tubules involves changes in cell shape, cell motility, and reorganization of the cytoskeleton. However, the exact intracellular mechanisms involved are far from understood. We have used the three-dimensional (3D) Madin-Darby canine kidney (MDCK) cell culture system to study how p21-activated kinase 1 (Pak1), which is an important regulator of the cytoskeleton, modulates branching. Our data reveal that Pak1 plays a crucial role in regulating branching morphogenesis. Expression of a dominant-negative Pak1 mutant (DN-Pak1) in MDCK cysts resulted in the spontaneous formation of extensions and branching tubules. Cellular contractility and levels of phosphorylated myosin light chain (pMLC) were increased in DN-Pak1 cells in collagen. Expression of a DN-Pak1 mutant that does not bind to PIX (DN-Pak1-ΔPIX) failed to form extensions in collagen and did not have increased contractility. This shows that the DN-Pak1 mutant requires PIX binding to generate extensions and increased contractility in 3D culture. Furthermore, a β1-integrin function-blocking antibody (AIIB2) inhibited the formation of branches and blocked the increased contractility in DN-Pak1 cysts. Taken together, our work shows that DN-Pak1-induced branching morphogenesis requires PIX binding and β1-integrin signaling.

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