- Prof. Marc F. Hoylaerts, PhD
- Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium.
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Special Issue Introduction
In 2005, the platelet aggregation receptor 1 (PEAR1) was described as a novel epidermal growth factor repeat-containing transmembrane growth receptor, highly expressed in platelets and endothelial cells. Initial studies demonstrated a role of PEAR1 in platelet activation, observations triggering many subsequent investigations in depth on its function in platelets and endothelial cells. In 2009, functional genomics studies underscored that a number of SNPs in PEAR1 are associated with increased response during platelet activation studies with collagen analogues and with increased PEAR1 protein expression after platelet degranulation. Numerous genome-wide analyses and targeted deep resequencing over the last 12 years have illustrated how various PEAR1 gene variants are associated with modifications in platelet aggregation in response to various agonists in health and cardiovascular disease, coupled to differences in PEAR1 expression. Extensive studies in 2012 on the mechanism of PEAR1 in platelet activation uncovered that, in resting platelets, the cytoplasmic tail of PEAR1 is complexed to c-Src and Fyn. During receptor activation with pseudo-ligands, PEAR1 is phosphorylated, phospho-PEAR1 in turn recruiting p85 PI3K, resulting in persistent activation of PI3K and Akt. Thus, αIIbβ3 activation was amplified, hence stabilizing platelet aggregates.
The parallel search for the biological ligand for platelet PEAR1 resulted in the identification on the platelet membrane of the high affinity immunoglobulin E (IgE) receptor subunit α (FcεR1α) as a PEAR1 ligand. FcεR1α and PEAR1 directly interact through their membrane-proximal Ig-like and 13th epidermal growth factor domains with a relatively strong affinity (KD ∼ 30 nm). Even when this interaction can explain the role of PEAR1 in platelet amplification during the collagen-induced platelet aggregation, interindividual contributions by this pathway are highly variable, justifying further quests for other biological ligands or co-receptors, to explain all the association findings for PEAR1 and platelet function in cardiovascular outcome.
Also in endothelial cells, PEAR1 seems to play a crucial role in the regulation of the PI3K/Akt regulation, but the mechanism is more complex, involving expression regulation of PTEN, which is a phosphatase, controlling the degree of Akt phosphorylation, events crucial in angiogenesis. In Pear1-/- mice, physiological blood vessel formation was unaffected, but neoangiogenesis in these mice was significantly increased both in a hind limb ischaemia ligation model and in a skin wound-healing model, resulting in a two-fold faster wound closure. Recent studies have demonstrated that PEAR1 can suppress proliferation of pulmonary microvascular endothelial cells via PI3K/Akt regulation, and that PEAR1 can regulate bovine muscle satellite cell migration and differentiation via integrin beta-1 and focal adhesion kinase. The molecular characterization in 2016 of the first platelet function-related CpG-SNP, which reinforces PEAR1 enhancer activity through allele-specific DNA methylation, further illustrates the complex genetic predisposition of particular SNPs, potentially directly impacting the expression of several genes, relevant for cell function.
Despite many association studies, linking PEAR1 gene variability to platelet function and cardiovascular disease, even when we understand the molecular pathways triggered by PEAR1, our knowledge on its relevance in cardiovascular health and disease is still too limited. This is even more so for the more complex role of PEAR1 in endothelial cells. This special issue, therefore, aims at compiling new insights that will extend our present understanding of PEAR1 in platelet and endothelial cell biology.
KeywordsPEAR1, platelet signaling, platelet receptor, angiogenesis, PI3K/Akt, PTEN
Submission Deadline15 May 2021