Faculty Opinions recommendation of Requirement of β1 integrin for endothelium-dependent vasodilation and collateral formation in hindlimb ischemia.

2020 ◽  
Author(s):  
David Wasserman
Keyword(s):  
Β1 Integrin ◽  
Hindlimb Ischemia ◽  
Collateral Formation

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.

scholarly journals Endothelial-Specific EphA4 Negatively Regulates Native Pial Collateral Formation and Re-Perfusion following Hindlimb Ischemia

PLoS ONE ◽  
2016 ◽  
Vol 11 (7) ◽  
pp. e0159930 ◽  
Author(s):  
Benjamin Okyere ◽  
Kaavya Giridhar ◽  
Amanda Hazy ◽  
Miao Chen ◽  
David Keimig ◽  
...  
Keyword(s):  
Hindlimb Ischemia ◽  
Collateral Formation

Cell-matrix interactions in the early mouse embryo

1992 ◽  
Vol 50 (1) ◽  
pp. 600-601
Author(s):  
A.E. Sutherland ◽  
P.G. Calarco ◽  
C.H. Damsky
Keyword(s):  
Mouse Embryo ◽  
Giant Cells ◽  
Blastocyst Stage ◽  
Integrin Subunit ◽  
Β1 Integrin ◽  
Cell Stage ◽  
Early Mouse Embryo ◽  
Migratory Activity ◽  
Early Mouse ◽  
Cell Matrix Interactions

Cell-extracellular matrix (ECM) interactions mediated by the integrin family of receptors are critical for morphogenesis and may also play a regulatory role in differentiation during early development. We have examined the onset of expression of individual integrin subunit proteins in the early mouse embryo, and their roles in early morphogenetic events. As detected by immunoprecipitation, the α6, αV, β1, and β3 subunits are detected as early as the 4-cell stage, α5 at the hatched blastocyst stage and αl and α3 following blastocyst attachment. We tested the role of these integrins in the attachment and migratory activity of two cell populations of the early mouse embryo: the trophoblast giant cells, which invade the uterine stroma and ultimately contribute to the chorio-allantoic placenta, and the parietal endoderm, which migrates over the inner surface of the trophoblast and ultimately forms Reichert's membrane and the parietal yolk sac. Experiments were done in serum-free medium on substrates coated with laminin (Ln) and fibronectin (Fn). Trophoblast outgrowth occurs on Ln and its E8 fragment (long arm), but not on the E1’ fragment (cross region) (Figs. 1, 2 ). This outgrowth is inhibited by anti-E8, anti-Ln, and by the anti-β1 family antiserum anti-ECMR, but not by anti-αV or the function-perturbing GoH3 antibody that recognizes the α6/β1 integrin, a major Ln (E8) receptor. This suggests that trophoblast outgrowth on Ln or E8 is mediated by a different β1 integrin such as α3/β1. Early stages of trophoblast outgrowth (up to 48 hours) on Fn are inhibited by anti-Fn and by function-perturbing anti-αV antibodies, whereas at later times outgrowth becomes insensitive to anti-αV but remains sensitive to the anti-β1 family antiserum anti-ECMr, indicating that trophoblast cells modulate their interaction with Fn during outgrowth. Trophoblast outgrowth on vitronectin (Vn) is sensitive to anti-αV antibodies throughout the 5-day period examined.

Laminin 521 Modulates the Сytotoxic Effect of 5-Fluorouracil on Colorectal Cancer HT29 Cells

2019 ◽  
Vol 35 (6) ◽  
pp. 73-79
Author(s):  
A. Turchinovich ◽  
I.M. Tsypina ◽  
V.G. Zgoda ◽  
S.V. Nikulin ◽  
D.V. Maltseva
Keyword(s):  
Colorectal Cancer ◽  
Cytotoxic Effect ◽  
Mechanisms Of Action ◽  
Ht29 Cell ◽  
Β1 Integrin ◽  
Russian Science ◽  
Apoptotic Gene ◽  
Ht29 Cells ◽  
First Time ◽  
Ht29 Cell Line

The cytotoxic effect of 5-fluorouracil (5FU) and regorafenib (RF)-drugs with different mechanisms of action used to treat colorectal cancer-on the HT29 cell line when cultured on plastic and laminin 521 (LM-521) has been studied. It was shown for the first time that LM-521 can increase the sensitivity of tumor cells to 5FU. Based on the analysis of the transcriptome and proteome, a possible mechanism of the observed effect of LM-521 on HT29 cell viability was proposed. The interaction of β1-containing integrins on the cell surface with LM-521 can activate the FAK/PI3K/Akt signaling pathways, promote phosphorylation of the YAP transcription coactivator and its binding to a complex with the 14-3-3σ protein. The formation of such complex leads to the YAP retention in the cytoplasm, prevents its transport to the nucleus and the activation of anti-apoptotic gene transcription. apoptosis, β1 integrin, colorectal cancer, laminin 521 (laminin-11), regorafenib, 5-fluorouracil, HT29, ITGB1, LAMA5, YAP, SFN, 14-3-3σ The study was funded by the Russian Science Foundation (Project 17-14-01338).

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 Human-Induced Pluripotent Stem-Cell-Derived Smooth Muscle Cells Increase Angiogenesis to Treat Hindlimb Ischemia

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 792
Author(s):  
Xixiang Gao ◽  
Mingjie Gao ◽  
Jolanta Gorecka ◽  
John Langford ◽  
Jia Liu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Smooth Muscle ◽  
Stem Cell ◽  
Smooth Muscle Cells ◽  
Functional Outcomes ◽  
Ethical Issues ◽  
Muscle Cells ◽  
Doppler Imaging ◽  
Hindlimb Ischemia ◽  
Induced Pluripotent

Induced pluripotent stem cells (iPSC) represent an innovative, somatic cell-derived, easily obtained and renewable stem cell source without considerable ethical issues. iPSC and their derived cells may have enhanced therapeutic and translational potential compared with other stem cells. We previously showed that human iPSC-derived smooth muscle cells (hiPSC-SMC) promote angiogenesis and wound healing. Accordingly, we hypothesized that hiPSC-SMC may be a novel treatment for human patients with chronic limb-threatening ischemia who have no standard options for therapy. We determined the angiogenic potential of hiPSC-SMC in a murine hindlimb ischemia model. hiPSC-SMC were injected intramuscularly into nude mice after creation of hindlimb ischemia. Functional outcomes and perfusion were measured using standardized scores, laser Doppler imaging, microCT, histology and immunofluorescence. Functional outcomes and blood flow were improved in hiPSC-SMC-treated mice compared with controls (Tarlov score, p < 0.05; Faber score, p < 0.05; flow, p = 0.054). hiPSC-SMC-treated mice showed fewer gastrocnemius fibers (p < 0.0001), increased fiber area (p < 0.0001), and enhanced capillary density (p < 0.01); microCT showed more arterioles (<96 μm). hiPSC-SMC treatment was associated with fewer numbers of macrophages, decreased numbers of M1-type (p < 0.05) and increased numbers of M2-type macrophages (p < 0.0001). Vascular endothelial growth factor (VEGF) expression in ischemic limbs was significantly elevated with hiPSC-SMC treatment (p < 0.05), and inhibition of VEGFR-2 with SU5416 was associated with fewer capillaries in hiPSC-SMC-treated limbs (p < 0.0001). hiPSC-SMC promote VEGF-mediated angiogenesis, leading to improved hindlimb ischemia. Stem cell therapy using iPSC-derived cells may represent a novel and potentially translatable therapy for limb-threatening ischemia.

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