Actin-binding proteins differentially regulate endothelial cell stiffness, ICAM-1 function and neutrophil transmigration

Schaefer, Antje; Riet, Joost te; Ritz, Katja; Hoogenboezem, Mark; Anthony, Eloise C.; Mul, Frederik P. J.; Vries, Carlie J.M. de; Daemen, Mat J.A.P.; Figdor, Carl G.; Buul, Jaap D. van; Hordijk, Peter L.

doi:10.1242/jcs.154708

Cited by 96 publications

(104 citation statements)

References 47 publications

(24 reference statements)

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“…Additionally, various actin-binding proteins can differentially regulate cell stiffness [32], indicating that the spatial organization of actin filaments is also crucial in the determination of stiffness.…”

Section: Actin Filamentsmentioning

confidence: 99%

Cell stiffness determined by atomic force microscopy and its correlation with cell motility

Luo

Kuang

Zhang

et al. 2016

Biochimica et Biophysica Acta (BBA) - General Subjects

157

139

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Section: Actin Filamentsmentioning

confidence: 99%

Cell stiffness determined by atomic force microscopy and its correlation with cell motility

Luo

Kuang

Zhang

et al. 2016

Biochimica et Biophysica Acta (BBA) - General Subjects

157

139

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“…Some studies reported that the periphery of ECs is stiffer when compared with the nuclear area. 60,71,72 Others found a different stiffness gradient, with the highest stiffness in the nuclear region. 73 Despite these apparent discrepancies, we postulate that during the scanning or crawling phase of transmigration, leukocytes sense and respond to endothelial stiffness gradients.…”

Section: Cross Talk Between Ec Stiffness and Leukocyte Behaviormentioning

confidence: 99%

“…We recently showed that endothelial actinbinding proteins, in particular α-actinin-4, control local EC stiffness. 72 α-Actinin4 connects surface ICAM-1 to the endothelial actin cytoskeleton. This locally increases EC stiffness, which further enhances clustering of ICAM-1.…”

Section: Cross Talk Between Ec Stiffness and Leukocyte Behaviormentioning

confidence: 99%

“…139 This suggests that the composition and stiffness of the subendothelial ECM, determined by several factors as discussed above, are directly reflected by the stiffness of the endothelium. Consequently, changes in vascular wall stiffness will be equally visible at the luminal side of the endothelium and are sensed by adherent leukocytes 72 and by adherent platelets. 140 The expression of collagens and of lysyl oxidase (Lox), an enzyme that cross links and strengthens ECM fibers, is strongly upregulated in VSMCs that are cultured on rigid substrates (25 kPa) when compared with cells on softer matrices.…”

Section: Extracellular Matrixmentioning

confidence: 99%

mentioning

confidence: 99%

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Between Rho(k) and a Hard Place

Huveneers

Daemen

Hordijk

2015

Circulation Research

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151

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Vascular stiffness is a mechanical property of the vessel wall that affects blood pressure, permeability, and inflammation. As a result, vascular stiffness is a key driver of (chronic) human disorders, including pulmonary arterial hypertension, kidney disease, and atherosclerosis. Responses of the endothelium to stiffening involve integration of mechanical cues from various sources, including the extracellular matrix, smooth muscle cells, and the forces that derive from shear stress of blood. This response in turn affects endothelial cell contractility, which is an important property that regulates endothelial stiffness, permeability, and leukocyte-vessel wall interactions. Moreover, endothelial stiffening reduces nitric oxide production, which promotes smooth muscle cell contraction and vasoconstriction. In fact, vessel wall stiffening, and microcirculatory endothelial dysfunction, precedes hypertension and thus underlies the development of vascular disease. Here, we review the cross talk among vessel wall stiffening, endothelial contractility, and vascular disease, which is controlled by Rho-driven actomyosin contractility and cellular mechanotransduction. In addition to discussing the various inputs and relevant molecular events in the endothelium, we address which actomyosin-regulated changes at cell adhesion complexes are genetically associated with human cardiovascular disease. Finally, we discuss recent findings that broaden therapeutic options for targeting this important mechanical signaling pathway in vascular pathogenesis. vascular stiffening) and the various external cues that regulate this. In addition, we will discuss the relationship between endothelial contractility and leukocyte extravasation and finally address (future) possibilities to therapeutically target ECs to reduce chronic, stiffness-related, vascular inflammation. Systemic Regulation of Vascular StiffnessArterial stiffness is strongly associated with high blood pressure, as well as with aging, and serves as an independent predictor of human cardiovascular disease. An elevation in arterial stiffness increases systolic blood pressure, thereby promoting cardiac hypertrophy, and decreases the diastolic blood pressure which is a trigger for developing myocardial ischemia. 7 Aortic stiffness also affects the microcirculation and vice versa, microcirculatory changes affect aortic stiffness. Stiffening of the aortic wall leads to increased pulse wave velocity (PWV) and premature reflected waves with elevated systolic and pulsatile central hemodynamic load resulting in microcirculatory damages in peripheral tissues. Conversely, microvasculature remodeling elevates systemic vascular resistance and pulse wave reflection, which stiffens the aortic wall, indicating that the endothelium has both a responsive and a causal role in vascular stiffening. 7 Increased PWV accurately estimates arterial wall stiffness and has recently been included in official hypertension guidelines. PWV values increase with age, and increases in aortic PWV is a g...

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Genetic Risk Factors Associated With Preeclampsia and Hypertensive Disorders of Pregnancy

et al. 2023

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ImportanceA genetic contribution to preeclampsia susceptibility has been established but is still incompletely understood.ObjectiveTo disentangle the underlying genetic architecture of preeclampsia and preeclampsia or other maternal hypertension during pregnancy with a genome-wide association study (GWAS) of hypertensive disorders of pregnancy.Design, Setting, and ParticipantsThis GWAS included meta-analyses in maternal preeclampsia and a combination phenotype encompassing maternal preeclampsia and preeclampsia or other maternal hypertensive disorders. Two overlapping phenotype groups were selected for examination, namely, preeclampsia and preeclampsia or other maternal hypertension during pregnancy. Data from the Finnish Genetics of Pre-eclampsia Consortium (FINNPEC, 1990-2011), Finnish FinnGen project (1964-2019), Estonian Biobank (1997-2019), and the previously published InterPregGen consortium GWAS were combined. Individuals with preeclampsia or other maternal hypertension during pregnancy and control individuals were selected from the cohorts based on relevant International Classification of Diseases codes. Data were analyzed from July 2020 to February 2023.ExposuresThe association of a genome-wide set of genetic variants and clinical risk factors was analyzed for the 2 phenotypes.ResultsA total of 16 743 women with prior preeclampsia and 15 200 with preeclampsia or other maternal hypertension during pregnancy were obtained from FINNPEC, FinnGen, Estonian Biobank, and the InterPregGen consortium study (respective mean [SD] ages at diagnosis: 30.3 [5.5], 28.7 [5.6], 29.7 [7.0], and 28 [not available] years). The analysis found 19 genome-wide significant associations, 13 of which were novel. Seven of the novel loci harbor genes previously associated with blood pressure traits (NPPA, NPR3, PLCE1, TNS2, FURIN, RGL3, and PREX1). In line with this, the 2 study phenotypes showed genetic correlation with blood pressure traits. In addition, novel risk loci were identified in the proximity of genes involved in the development of placenta (PGR, TRPC6, ACTN4, and PZP), remodeling of uterine spiral arteries (NPPA, NPPB, NPR3, and ACTN4), kidney function (PLCE1, TNS2, ACTN4, and TRPC6), and maintenance of proteostasis in pregnancy serum (PZP).Conclusions and RelevanceThe findings indicate that genes related to blood pressure traits are associated with preeclampsia, but many of these genes have additional pleiotropic effects on cardiometabolic, endothelial, and placental function. Furthermore, several of the associated loci have no known connection with cardiovascular disease but instead harbor genes contributing to maintenance of successful pregnancy, with dysfunctions leading to preeclampsialike symptoms.

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Actin-binding proteins differentially regulate endothelial cell stiffness, ICAM-1 function and neutrophil transmigration

Cited by 96 publications

References 47 publications

Cell stiffness determined by atomic force microscopy and its correlation with cell motility

Cell stiffness determined by atomic force microscopy and its correlation with cell motility

Between Rho(k) and a Hard Place

Genetic Risk Factors Associated With Preeclampsia and Hypertensive Disorders of Pregnancy

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