scholarly journals Revisiting PI3-kinase signalling in angiogenesis

2019 ◽  
Vol 1 (1) ◽  
pp. H125-H134 ◽  
Author(s):  
Piotr Kobialka ◽  
Mariona Graupera
Keyword(s):  
Blood Vessel ◽  
Cell Function ◽  
Vascular Malformations ◽  
Pi3k Pathway ◽  
Current View ◽  
Endothelial Cell Function ◽  
Vesicular Traffic ◽  
Sprouting Angiogenesis ◽  
Vessel Growth ◽  
Pi3k Signalling

PI3Ks belong to a family of lipid kinases that comprises eight isoforms. They phosphorylate the third position of the inositol ring present in phosphatidylinositol lipids and, in turn, activate a broad range of proteins. The PI3K pathway regulates primal cellular responses, including proliferation, migration, metabolism and vesicular traffic. These processes are fundamental for endothelial cell function during sprouting angiogenesis, the most common type of blood vessel formation. Research in animal models has revealed key functions of PI3K family members and downstream effectors in angiogenesis. In addition, perturbations in PI3K signalling have been associated with aberrant vascular growth including tumour angiogenesis and vascular malformations. Together, this highlights that endothelial cells are uniquely sensitive to fluctuations in PI3K signalling. Here, we aim to update the current view on this important signalling cue in physiological and pathological blood vessel growth.

scholarly journals p21-Activated Kinase 2 Regulates Endothelial Development and Function through the Bmk1/Erk5 Pathway

2015 ◽  
Vol 35 (23) ◽  
pp. 3990-4005 ◽  
Author(s):  
Maria Radu ◽  
Karen Lyle ◽  
Klaus P. Hoeflich ◽  
Olga Villamar-Cruz ◽  
Hartmut Koeppen ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Blood Vessel ◽  
Cell Function ◽  
Early Embryo ◽  
Endothelial Cell Function ◽  
Adult Mice ◽  
P21 Activated Kinase ◽  
And Migration ◽  
And Function ◽  
Cytoskeleton Rearrangements

p21-activated kinases (Paks) have been shown to regulate cytoskeleton rearrangements, cell proliferation, attachment, and migration in a variety of cellular contexts, including endothelial cells. However, the role of endothelial Pak in embryo development has not been reported, and currently, there is no consensus on the endothelial function of individual Pak isoforms, in particular p21-activated kinase 2 (Pak2), the main Pak isoform expressed in endothelial cells. In this work, we employ genetic and molecular studies that show that Pak2, but not Pak1, is a critical mediator of development and maintenance of endothelial cell function. Endothelial depletion of Pak2 leads to early embryo lethality due to flawed blood vessel formation in the embryo body and yolk sac. In adult endothelial cells, Pak2 depletion leads to severe apoptosis and acute angiogenesis defects, and in adult mice, endothelial Pak2 deletion leads to increased vascular permeability. Furthermore, ubiquitous Pak2 deletion is lethal in adult mice. We show that many of these defects are mediated through a newly unveiled Pak2/Bmk1 pathway. Our results demonstrate that endothelial Pak2 is essential during embryogenesis and also for adult blood vessel maintenance, and they also pinpoint the Bmk1/Erk5 pathway as a critical mediator of endothelial Pak2 signaling.

Abstract 18412: Long Non-coding RNA Meg3 Regulates Senescence-associated Genes and Controls Endothelial Cell Function

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Reinier Boon ◽  
Patrick Hofmann ◽  
Katharina Michalik ◽  
Andrea Knau ◽  
Yuliya Ponomareva ◽  
...  
Keyword(s):  
Gene Expression ◽  
Endothelial Cells ◽  
Cell Function ◽  
Regulation Of Gene Expression ◽  
Global Gene Expression ◽  
Exon Array ◽  
Protein Coding ◽  
Endothelial Cell Function ◽  
Sprouting Angiogenesis

The majority of transcribed RNAs does not encode proteins, but function as regulatory RNAs. Non-protein-coding RNA are classified in short (<200 nt) and long (>200 nt) non-coding RNAs (lncRNAs). lncRNAs have been described to play an important role in many biological processes, including epigenetic regulation of gene expression. To determine the expression and functional role of lncRNAs in endothelial cells, we performed RNA deep sequencing of human umbilical venous endothelial cells (ECs). Among the highest expressed lncRNAs, we identified Maternally Expressed 3 (Meg3, 35.3±0.6 RPKM), which has been correlated to VEGF expression. In HUVECs, Meg3 localizes to the nucleus and is induced by hypoxia (4.08±0.78-fold, p<0.05). Interestingly, Meg3 was also found to be induced in the intima of aged mice and correlates with age in human hearts (p=0.016). Meg3 levels are also induced in replicative senescent HUVECs in vitro (passage 16/17 vs 2/3, 2.9±0.99-fold).Conversely, silencing of Meg3 using LNA-GapmeRs induced angiogenic sprouting of endothelial cells in vitro (1.4±0.14-fold, P<0.05) but did not affect caspase-3 activation. Mechanistically, RNA immunoprecipations showed that Meg3 associates specifically to H3K27me3, a silencing chromatin mark. Silencing of Meg3 in HUVECs induces a robust repression of global gene expression, as measured by exon array analysis, with a highly significant repression of the anti-senescent HMGA2. In summary these results demonstrate, that the lncRNA Meg3 is highly expressed in endothelial cells and is up-regulated by hypoxia and aging. Functionally, Meg3 inhibits sprouting angiogenesis in vitro. Meg3 depletion leads to a general repression of gene expression and the senescence marker HMGA2 likely by inducing the recruitment of silencing H3K27me3 marks to the promoters Therefore, modulating Meg3 may be a potential strategy to reduce endothelial senescence or increase regenerative angiogenesis.

scholarly journals Long Noncoding RNA MALAT1 Regulates Endothelial Cell Function and Vessel Growth

2014 ◽  
Vol 114 (9) ◽  
pp. 1389-1397 ◽  
Author(s):  
Katharina M. Michalik ◽  
Xintian You ◽  
Yosif Manavski ◽  
Anuradha Doddaballapur ◽  
Martin Zörnig ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Cell Function ◽  
Endothelial Cell Function ◽  
Vessel Growth

Do DPP-4 inhibitors improve endothelial cell function?

2017 ◽  
Vol 01 (01) ◽  
Author(s):  
Hiroshi Nomoto ◽  
Hideaki Miyoshi ◽  
Akinobu Nakamura ◽  
Tatsuya Atsumi ◽  
Naoki Manda ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Cell Function ◽  
Endothelial Cell Function

Estrogen Restores Endothelial Cell Function in an Experimental Model of Vascular Injury

Circulation ◽  
1997 ◽  
Vol 96 (5) ◽  
pp. 1624-1630 ◽  
Author(s):  
C. Roger White ◽  
Jonathan Shelton ◽  
Shi-Juan Chen ◽  
Victor Darley-Usmar ◽  
Leslie Allen ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Experimental Model ◽  
Vascular Injury ◽  
Cell Function ◽  
Endothelial Cell Function

scholarly journals CD40/CD40L contributes to hypercholesterolemia-induced microvascular inflammation

2009 ◽  
Vol 296 (3) ◽  
pp. H689-H697 ◽  
Author(s):  
Karen Y. Stokes ◽  
LeShanna Calahan ◽  
Candiss M. Hamric ◽  
Janice M. Russell ◽  
D. Neil Granger
Keyword(s):  
Oxidative Stress ◽  
T Cells ◽  
T Cell ◽  
Blood Cell ◽  
Cell Function ◽  
Inflammatory Responses ◽  
Microvascular Dysfunction ◽  
Cd40 Ligand ◽  
Scid Mice ◽  
Endothelial Cell Function

Hypercholesterolemia is associated with phenotypic changes in endothelial cell function that lead to a proinflammatory and prothrombogenic state in different segments of the microvasculature. CD40 ligand (CD40L) and its receptor CD40 are ubiquitously expressed and mediate inflammatory responses and platelet activation. The objective of this study was to determine whether CD40/CD40L, in particular T-cell CD40L, contributes to microvascular dysfunction induced by hypercholesterolemia. Intravital microscopy was used to quantify blood cell adhesion in cremasteric postcapillary venules, endothelium-dependent vasodilation responses in arterioles, and microvascular oxidative stress in wild-type (WT) C57BL/6, CD40-deficient (−/−), CD40L−/−, or severe combined immune deficient (SCID) mice placed on a normal (ND) or high-cholesterol (HC) diet for 2 wk. WT-HC mice exhibited an exaggerated leukocyte and platelet recruitment in venules and impaired vasodilation responses in arterioles compared with ND counterparts. A deficiency of CD40, CD40L, or lymphocytes attenuated these responses to HC. The HC phenotype was rescued in CD40L−/− and SCID mice by a transfer of WT T cells. Bone marrow chimeras revealed roles for both vascular- and blood cell-derived CD40 and CD40L in the HC-induced vascular responses. Hypercholesterolemia induced an oxidative stress in both arterioles and venules of WT mice, which was abrogated by either CD40 or CD40L deficiency. The transfer of WT T cells into CD40L−/− mice restored the oxidative stress. These results implicate CD40/CD40L interactions between circulating cells and the vascular wall in both the arteriolar and venular dysfunction elicited by hypercholesterolemia and identify T-cell-associated CD40L as a key mediator of these responses.

scholarly journals Investigation of Wall Shear Stress in Cardiovascular Research and in Clinical Practice—From Bench to Bedside

2021 ◽  
Vol 22 (11) ◽  
pp. 5635
Author(s):  
Katharina Urschel ◽  
Miyuki Tauchi ◽  
Stephan Achenbach ◽  
Barbara Dietel
Keyword(s):  
Endothelial Cells ◽  
Shear Stress ◽  
Wall Shear Stress ◽  
Cell Function ◽  
Computational Techniques ◽  
Apical Surface ◽  
Cardiovascular Research ◽  
Endothelial Cell Function ◽  
Wall Shear

In the 1900s, researchers established animal models experimentally to induce atherosclerosis by feeding them with a cholesterol-rich diet. It is now accepted that high circulating cholesterol is one of the main causes of atherosclerosis; however, plaque localization cannot be explained solely by hyperlipidemia. A tremendous amount of studies has demonstrated that hemodynamic forces modify endothelial athero-susceptibility phenotypes. Endothelial cells possess mechanosensors on the apical surface to detect a blood stream-induced force on the vessel wall, known as “wall shear stress (WSS)”, and induce cellular and molecular responses. Investigations to elucidate the mechanisms of this process are on-going: on the one hand, hemodynamics in complex vessel systems have been described in detail, owing to the recent progress in imaging and computational techniques. On the other hand, investigations using unique in vitro chamber systems with various flow applications have enhanced the understanding of WSS-induced changes in endothelial cell function and the involvement of the glycocalyx, the apical surface layer of endothelial cells, in this process. In the clinical setting, attempts have been made to measure WSS and/or glycocalyx degradation non-invasively, for the purpose of their diagnostic utilization. An increasing body of evidence shows that WSS, as well as serum glycocalyx components, can serve as a predicting factor for atherosclerosis development and, most importantly, for the rupture of plaques in patients with high risk of coronary heart disease.

scholarly journals Vascular adaptation in pregnancy and endothelial dysfunction in preeclampsia

2017 ◽  
Vol 232 (1) ◽  
pp. R27-R44 ◽  
Author(s):  
D S Boeldt ◽  
I M Bird
Keyword(s):  
Endothelial Cell ◽  
Endothelial Dysfunction ◽  
Cell Function ◽  
Endothelial Cell Dysfunction ◽  
Hypertensive Disorders Of Pregnancy ◽  
Endothelial Cell Function ◽  
Vascular Adaptation ◽  
Cell Dysfunction ◽  
Maternal Adaptation ◽  
Flow Through

Maternal vascular adaptation to pregnancy is critically important to expand the capacity for blood flow through the uteroplacental unit to meet the needs of the developing fetus. Failure of the maternal vasculature to properly adapt can result in hypertensive disorders of pregnancy such as preeclampsia (PE). Herein, we review the endocrinology of maternal adaptation to pregnancy and contrast this with that of PE. Our focus is specifically on those hormones that directly influence endothelial cell function and dysfunction, as endothelial cell dysfunction is a hallmark of PE. A variety of growth factors and cytokines are present in normal vascular adaptation to pregnancy. However, they have also been shown to be circulating at abnormal levels in PE pregnancies. Many of these factors promote endothelial dysfunction when present at abnormal levels by acutely inhibiting key Ca2+ signaling events and chronically promoting the breakdown of endothelial cell–cell contacts. Increasingly, our understanding of how the contributions of the placenta, immune cells, and the endothelium itself promote the endocrine milieu of PE is becoming clearer. We then describe in detail how the complex endocrine environment of PE affects endothelial cell function, why this has contributed to the difficulty in fully understanding and treating this disorder, and how a focus on signaling convergence points of many hormones may be a more successful treatment strategy.

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