Platelet endothelial aggregation receptor-1: a novel modifier of neoangiogenesis

Vandenbriele, Christophe; Kauskot, Alexandre; Vandersmissen, Ine; Criel, Maarten; Geenens, Rachel; Craps, Sander; Luttun, Aernout; Janssens, Stefan; Hoylaerts, Marc; Verhamme, Peter

doi:10.1093/cvr/cvv193

Cited by 40 publications

(62 citation statements)

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“…Among patients with coronary heart disease taking antiplatelet agents [5], rs12041331 A -allele carriers experienced more adverse cardiovascular outcomes and had higher death rates than GG homozygotes. Moreover, in experimental studies [7], we observed an inverse correlation between endothelial PEAR1 expression and vascular assembly. In the Heredity and Phenotype Intervention Heart Study [8], there was significant association between flow-mediated dilation and rs12041331 .…”

Section: Introductionmentioning

confidence: 81%

PEAR1 is not a major susceptibility gene for cardiovascular disease in a Flemish population

et al. 2017

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BackgroundPlatelet Endothelial Aggregation Receptor 1 (PEAR1), a membrane protein highly expressed in platelets and endothelial cells, plays a role in platelet contact-induced activation, sustained platelet aggregation and endothelial function. Previous reports implicate PEAR1 rs12041331 as a variant influencing risk in patients with coronary heart disease. We investigated whether genetic variation in PEAR1 predicts cardiovascular outcome in a white population.MethodsIn 1938 participants enrolled in the Flemish Study on Environment, Genes and Health Outcomes (51.3% women; mean age 43.6 years), we genotyped 9 tagging SNPs in PEAR1, measured baseline cardiovascular risk factors, and recorded Cardiovascular disease incidence. For SNPs, we contrasted cardiovascular disease incidence of minor-allele heterozygotes and homozygotes (variant) vs. major-allele homozygotes (reference) and for haplotypes carriers vs. non-carriers. In adjusted analyses, we accounted for family clusters and baseline covariables, including sex, age, body mass index, mean arterial pressure, the total-to-HDL cholesterol ratio, smoking and drinking, antihypertensive drug treatment, and history of cardiovascular disease and diabetes mellitus.ResultsOver a median follow-up of 15.3 years, 238 died and 181 experienced a major cardiovascular endpoint. The multivariable-adjusted hazard ratios of eight PEAR1 SNPs, including rs12566888, ranged from 0.87 to 1.07 (P ≥0.35) and from 0.78 to 1.30 (P ≥0.15), respectively. The hazard ratios of three haplotypes with frequency ≥10% ranged from 0.93 to 1.11 (P ≥0.49) for mortality and from 0.84 to 1.03 (P ≥0.29) for a cardiovascular complications. These results were not influenced by intake of antiplatelet drugs, nonsteroidal anti-inflammatory drugs, or both (P-values for interaction ≥ 0.056).ConclusionsIn a White population, we could not replicate previous reports from experimental studies or obtained in patients suggesting that PEAR1 might be a susceptibility gene for cardiovascular complications.Electronic supplementary materialThe online version of this article (doi:10.1186/s12881-017-0411-x) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 81%

PEAR1 is not a major susceptibility gene for cardiovascular disease in a Flemish population

et al. 2017

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“…In endothelial cells, PEAR1 is a modulator of cell proliferation during neoangiogenesis. 36 With respect to its role in platelets, genomewide analysis has identified genetic variations in PEAR1 associated with altered responses during platelet aggregation by various agonists. 37 Certain PEAR1 gene haplotypes were strongly associated with human platelet integrin a IIb b 3 activation and P-selectin expression upon GPVI stimulation, and, in various ethnicities, several PEAR1 single-nucleotide polymorphisms have been associated with increased platelet aggregation for 1 allele, coupled to a higher platelet PEAR1 expression.…”

Section: Discussionmentioning

confidence: 99%

Synthetic glycopolymers and natural fucoidans cause human platelet aggregation via PEAR1 and GPIbα

et al. 2019

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Fucoidans are sulfated fucose-based polysaccharides that activate platelets and have pro- and anticoagulant effects; thus, they may have therapeutic value. In the present study, we show that 2 synthetic sulfated α-l-fucoside-pendant glycopolymers (with average monomeric units of 13 and 329) and natural fucoidans activate human platelets through a Src- and phosphatidylinositol 3-kinase (PI3K)–dependent and Syk-independent signaling cascade downstream of the platelet endothelial aggregation receptor 1 (PEAR1). Synthetic glycopolymers and natural fucoidan stimulate marked phosphorylation of PEAR1 and Akt, but not Syk. Platelet aggregation and Akt phosphorylation induced by natural fucoidan and synthetic glycopolymers are blocked by a monoclonal antibody to PEAR1. Direct binding of sulfated glycopolymers to epidermal like growth factor (EGF)–like repeat 13 of PEAR1 was shown by avidity-based extracellular protein interaction screen technology. In contrast, synthetic glycopolymers and natural fucoidans activate mouse platelets through a Src- and Syk-dependent pathway regulated by C-type lectin-like receptor 2 (CLEC-2) with only a minor role for PEAR1. Mouse platelets lacking the extracellular domain of GPIbα and human platelets treated with GPIbα-blocking antibodies display a reduced aggregation response to synthetic glycopolymers. We found that synthetic sulfated glycopolymers bind directly to GPIbα, substantiating that GPIbα facilitates the interaction of synthetic glycopolymers with CLEC-2 or PEAR1. Our results establish PEAR1 as the major signaling receptor for natural fucose-based polysaccharides and synthetic glycopolymers in human, but not in mouse, platelets. Sulfated α-l-fucoside-pendant glycopolymers are unique tools for further investigation of the physiological role of PEAR1 in platelets and beyond.

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“…5,6 PEAR1 knock-down in CD34 1 hematopoietic stem cells (HSCs) enhances megakaryopoietic progenitor proliferation, 4 while in endothelial cells, it is implicated in the regulation of neo-angiogenesis. 7 Both processes occur in a PI3K/PTEN-dependent manner.…”

Section: Introductionmentioning

confidence: 99%

Allele-specific DNA methylation reinforces PEAR1 enhancer activity

Izzi

Pistoni

Cludts

et al. 2016

Blood

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Key Points• Rs12041331 is the first functional CpG-SNP related to platelet function whose regulatory mechanism depends on DNA methylation. • Rs12041331 marks allelespecific methylation at the CpG island encompassing the first untranslated exon during megakaryopoiesis.Genetic variation in the PEAR1 locus is linked to platelet reactivity and cardiovascular disease. The major G allele of rs12041331, an intronic cytosine guanine dinucleotide-single-nucleotide polymorphism (CpG-SNP), is associated with higher PEAR1 expression in platelets and endothelial cells than the minor A allele. The molecular mechanism underlying this difference remains elusive. We have characterized the histone modification profiles of the intronic region surrounding rs12041331 and identified H3K4Me1 enhancer-specific enrichment for the region that covers the CpG-SNP. Interestingly, methylation studies revealed that the CpG site is fully methylated in leukocytes of GG carriers. Nuclear protein extracts from megakaryocytes, endothelial cells, vs control HEK-293 cells show a 3-fold higher affinity for the methylated G allele compared with nonmethylated G or A alleles in a gel electrophoretic mobility shift assay. To understand the positive relationship between methylation and gene expression, we studied DNA methylation at 4 different loci of PEAR1 during in vitro megakaryopoiesis. During differentiation, the CpG-SNP remained fully methylated, while we observed rapid methylation increases at the CpG-island overlapping the first 59-untranslated region exon, paralleling the increased PEAR1 expression. In the same region, A-allele carriers of rs12041331 showed significantly lower DNA methylation at CGI1 compared with GG homozygote. This CpG-island contains binding sites for the methylation-sensitive transcription factor CTCF, whose binding is known to play a role in enhancer activation and/or repression. In conclusion, we report the molecular characterization of the first platelet function-related CpG-SNP, a genetic predisposition that reinforces PEAR1 enhancer activity through allele-specific DNA methylation. (Blood. 2016;128(7):1003-1012

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Platelet endothelial aggregation receptor-1: a novel modifier of neoangiogenesis

Abstract: We established an inverse correlation between endothelial PEAR1 expression and vascular assembly both in vitro and in vivo. These findings identify PEAR1 as a novel modifier of neoangiogenesis.

Cited by 40 publications

References 59 publications

PEAR1 is not a major susceptibility gene for cardiovascular disease in a Flemish population

PEAR1 is not a major susceptibility gene for cardiovascular disease in a Flemish population

Synthetic glycopolymers and natural fucoidans cause human platelet aggregation via PEAR1 and GPIbα

Allele-specific DNA methylation reinforces PEAR1 enhancer activity

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