Endothelial nitric oxide synthase activation is required for heparin receptor effects on vascular smooth muscle cells

Li, Yaqiu; Talotta-Altenburg, Leanna M.; Silimperi, Kayli A.; Ciabattoni, Grace O.; Lowe-Krentz, Linda J.

doi:10.1152/ajpcell.00284.2018

Cited by 9 publications

(6 citation statements)

References 65 publications

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“…The increase in fluid shear stress force is transmitted to the SMC by diffusible molecules such as nitric oxide (NO) [ 93 ]. NO is synthesized by endothelial nitric oxide synthase (eNOS) or inducible nitric oxide synthase (iNOS) [ 94 ].…”

Section: The Effect Of Hemodynamics On Smooth Muscle Cell Phenotype During Arteriogenesismentioning

confidence: 99%

Role of Vascular Smooth Muscle Cell Phenotype Switching in Arteriogenesis

Ashraf

Zen

2021

IJMS

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Arteriogenesis is one of the primary physiological means by which the circulatory collateral system restores blood flow after significant arterial occlusion in peripheral arterial disease patients. Vascular smooth muscle cells (VSMCs) are the predominant cell type in collateral arteries and respond to altered blood flow and inflammatory conditions after an arterial occlusion by switching their phenotype between quiescent contractile and proliferative synthetic states. Maintaining the contractile state of VSMC is required for collateral vascular function to regulate blood vessel tone and blood flow during arteriogenesis, whereas synthetic SMCs are crucial in the growth and remodeling of the collateral media layer to establish more stable conduit arteries. Timely VSMC phenotype switching requires a set of coordinated actions of molecular and cellular mediators to result in an expansive remodeling of collaterals that restores the blood flow effectively into downstream ischemic tissues. This review overviews the role of VSMC phenotypic switching in the physiological arteriogenesis process and how the VSMC phenotype is affected by the primary triggers of arteriogenesis such as blood flow hemodynamic forces and inflammation. Better understanding the role of VSMC phenotype switching during arteriogenesis can identify novel therapeutic strategies to enhance revascularization in peripheral arterial disease.

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Section: The Effect Of Hemodynamics On Smooth Muscle Cell Phenotype During Arteriogenesismentioning

confidence: 99%

Role of Vascular Smooth Muscle Cell Phenotype Switching in Arteriogenesis

Ashraf

Zen

2021

IJMS

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“…The heparin receptor, Tmem184a, was identified in vascular ECs (Farwell et al, 2016). Tmem184a is responsible for the antiproliferative signaling cascades induced by heparin in vitro (Gilotti et al, 2014;Pugh et al, 2016;Li et al, 2020). Previous in vivo studies show that Tmem184a is required for proper vascular regeneration length in the adult regenerating zebrafish caudal fin (Farwell et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

“…The heparin receptor, Tmem184a, was identified in vascular cells (Farwell et al, 2016;Pugh et al, 2016) with a putative heparin binding domain at the C-terminal region of the protein. Heparin binds specifically to Tmem184a which is required for anti-proliferative signaling cascades induced by heparin treatment of vascular cells in vitro (Gilotti et al, 2014;Farwell et al, 2016;Pugh et al, 2016;Li et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Involvement of transmembrane protein 184a during angiogenesis in zebrafish embryos

et al. 2022

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Angiogenesis, the outgrowth of new blood vessels from existing vasculature, is critical during development, tissue formation, and wound healing. In response to vascular endothelial growth factors (VEGFs), endothelial cells are activated to proliferate and move towards the signal, extending the vessel. These events are directed by VEGF-VEGF receptor (Vegfr2) signal transduction, which in turn is modulated by heparan sulfate proteoglycans (HSPGs). HSPGs are glycoproteins covalently attached to HS glycosaminoglycan chains. Transmembrane protein 184a (Tmem184a) has been recently identified as a heparin receptor, which is believed to bind heparan sulfate chains in vivo. Therefore, Tmem184a has the potential to fine-tune interactions between VEGF and HS, modulating Vegfr2-dependent angiogenesis. The function of Tmem184a has been investigated in the regenerating zebrafish caudal fin, but its role has yet to be evaluated during developmental angiogenesis. Here we provide insights into how Tmem184a contributes to the proper formation of the vasculature in zebrafish embryos. First, we find that knockdown of Tmem184a causes a reduction in the number of intact intersegmental vessels (ISVs) in the zebrafish embryo. This phenotype mimics that of vegfr2b knockout mutants, which have previously been shown to exhibit severe defects in ISV development. We then test the importance of HS interactions by removing the binding domain within the Tmem184a protein, which has a negative effect on angiogenesis. Tmem184a is found to act synergistically with Vegfr2b, indicating that the two gene products function in a common pathway to modulate angiogenesis. Moreover, we find that knockdown of Tmem184a leads to an increase in endothelial cell proliferation but a decrease in the amount of VE-cadherin present. Together, these findings suggest that Tmem184a is necessary for ISVs to organize into mature, complete vessels.

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“…Likewise, heparin binds to β2GPI in domain V through an interaction with Lys284, Lys286, and Lys287, and decreases the ability to recognize aPL aβ2GPI by reducing their prothrombotic activity ( Guerin et al, 2002 ). Similar to HCQ, heparin increases the phosphorylation of eNOS, thus increasing NO ( Li et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Differences in Endothelial Activation and Dysfunction Induced by Antiphospholipid Antibodies Among Groups of Patients With Thrombotic, Refractory, and Non-refractory Antiphospholipid Syndrome

et al. 2021

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Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by pregnancy morbidity or thrombosis and persistent antiphospholipid antibodies (aPL) that bind to the endothelium and induce endothelial activation, which is evidenced by the expression of adhesion molecules and the production of reactive oxygen species (ROS) and subsequent endothelial dysfunction marked by a decrease in the synthesis and release of nitric oxide (NO). These endothelial alterations are the key components for the development of severe pathological processes in APS. Patients with APS can be grouped according to the presence of other autoimmune diseases (secondary APS), thrombosis alone (thrombotic APS), pregnancy morbidity (obstetric APS), and refractoriness to conventional treatment regimens (refractory APS). Typically, patients with severe and refractory obstetric APS exhibit thrombosis and are classified as those having primary or secondary APS. The elucidation of the mechanisms underlying these alterations according to the different groups of patients with APS could help establish new therapies, particularly necessary for severe and refractory cases. Therefore, this study aimed to evaluate the differences in endothelial activation and dysfunction induced by aPL between patients with refractory obstetric APS and other APS clinical manifestations. Human umbilical vein endothelial cells (HUVECs) were stimulated with polyclonal immunoglobulin-G (IgG) from different groups of patients n = 21), including those with primary (VTI) and secondary thrombotic APS (VTII) and refractory primary (RI+), refractory secondary (RII+), and non-refractory primary (NR+) obstetric APS. All of them with thrombosis. The expression of adhesion molecules; the production of ROS, NO, vascular endothelial growth factor (VEGF), and endothelin-1; and the generation of microparticles were used to evaluate endothelial activation and dysfunction. VTI IgG induced the expression of adhesion molecules and the generation of microparticles and VEGF. RI+ IgG induced the expression of adhesion molecules and decreased NO production. RII+ IgG increased the production of microparticles, ROS, and endothelin-1 and reduced NO release. NR+ IgG increased the production of microparticles and endothelin-1 and decreased the production of VEGF and NO. These findings reveal differences in endothelial activation and dysfunction among groups of patients with APS, which should be considered in future studies to evaluate new therapies, especially in refractory cases.

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Endothelial nitric oxide synthase activation is required for heparin receptor effects on vascular smooth muscle cells

Cited by 9 publications

References 65 publications

Role of Vascular Smooth Muscle Cell Phenotype Switching in Arteriogenesis

Role of Vascular Smooth Muscle Cell Phenotype Switching in Arteriogenesis

Involvement of transmembrane protein 184a during angiogenesis in zebrafish embryos

Differences in Endothelial Activation and Dysfunction Induced by Antiphospholipid Antibodies Among Groups of Patients With Thrombotic, Refractory, and Non-refractory Antiphospholipid Syndrome

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