The Interplay of Endothelial P2Y Receptors in Cardiovascular Health: From Vascular Physiology to Pathology

Q: What is the clinical evidence from this study?

Study design: Review. Population: Cardiovascular disease, atherosclerosis, and vascular remodeling. Intervention: Endothelial purinergic P2Y receptors (P2Y1-R, P2Y2-R, P2Y12-R).

Q: What does this research mean for the field?

Endothelial P2Y1 and P2Y2 receptors mediate NO-dependent vasorelaxation and vascular repair, while also promoting vascular inflammation and atherosclerosis in preclinical models. Novelty: ClaimNovelty.SYNTHESIS. Consensus alignment: ConsensusAlignment.NEUTRAL.

Cendrine Cabou; Laurent O. Martinez

doi:10.3390/ijms23115883

May 24, 2022International Journal of Molecular SciencesOpen Access

The Interplay of Endothelial P2Y Receptors in Cardiovascular Health: From Vascular Physiology to Pathology

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Key result

Endothelial P2Y1 and P2Y2 receptors mediate vasorelaxation yet promote atherosclerosis in preclinical models.

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Why the study?

Better characterization of the role of endothelial purinergic P2Y receptors and downstream signaling pathways in healthy and pathological environments has clinical potential for preventing and treating cardiovascular diseases.

Key Points

To synthesize preclinical evidence on how endothelial purinergic P2Y receptors modulate vascular physiology and to evaluate their dual protective and pathological roles in cardiovascular disease.
Narrative review synthesizing preclinical in vitro experiments using human umbilical vein endothelial cells (HUVECs) and microvascular endothelial cells (HMEC-1).
Analysis of endothelial-specific knockout and transgenic mouse models, including ApoE and LDLr-deficient strains.
Evaluation of downstream G-protein signaling pathways, lipid transcytosis mechanisms, and clinical antiplatelet agents targeting P2Y1-R, P2Y2-R, and P2Y12-R.
Endothelial P2Y1-R and P2Y2-R stimulate nitric oxide-dependent vasorelaxation as well as endothelial cell proliferation and migration during endothelial repair.
Endothelial P2Y2-R promotes vascular inflammation via NF-κB, neointimal hyperplasia, and atheroma formation, with P2Y2-R deletion protecting ApoE and LDLr knockout mice from atherogenesis.
Endothelial P2Y12-R stimulates high-density lipoprotein (HDL) transcytosis to limit vascular wall lipid deposition, while P2Y12-R antagonists alter cell proliferation and modulate thrombospondin-1 release.

Structured PICO

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Population

Preclinical models including cultured endothelial cells (HUVECs, BAECs, HUAECs, HMEC-1, mouse lung endothelial cells), isolated human veins, and rodent models (wild-type, ApoE-KO, LDLr-KO, P2Y1-KO, and endothelial-specific P2Y2-KO or Gq/11-KO mice)

Characterizing how endothelial P2Y receptor subtypes (P2Y1, P2Y2, P2Y12) balance protective nitric oxide-mediated vasorelaxation and HDL transcytosis against pathological vascular inflammation and atherogenesis offers potential therapeutic targets for cardiovascular disease.

Limitations

In vitro observations regarding angiogenic properties of purinergic P2Y-R remain to be reproduced in vivo under physiological or pathological conditions.
Studies investigating the selective contribution of endothelial P2Y-R subtypes to vascular inflammation and atherosclerosis are few and limited to mouse models.
The cell signaling pathway downstream of endothelial P2Y12-R activation in HDL transcytosis and its in vivo functionality in atherosclerosis remain to be unraveled.
In vitro observations of P2Y-R angiogenic and repair properties remain to be reproduced in vivo under physiological or pathological conditions.
The downstream signaling pathways and in vivo relevance of P2Y12-R-mediated HDL transcytosis in endothelial dysfunction or atherosclerosis remain to be unraveled.

Implication

May inform selective P2Y modulators for vascular disease; leaves open clinical validation from preclinical models.

Abstract

The endothelium plays a key role in blood vessel health. At the interface of the blood, it releases several mediators that regulate local processes that protect against the development of cardiovascular disease. In this interplay, there is increasing evidence for a role of extracellular nucleotides and endothelial purinergic P2Y receptors (P2Y-R) in vascular protection. Recent advances have revealed that endothelial P2Y1-R and P2Y2-R mediate nitric oxide-dependent vasorelaxation as well as endothelial cell proliferation and migration, which are processes involved in the regeneration of damaged endothelium. However, endothelial P2Y2-R, and possibly P2Y1-R, have also been reported to promote vascular inflammation and atheroma development in mouse models, with endothelial P2Y2-R also being described as promoting vascular remodeling and neointimal hyperplasia. Interestingly, at the interface with lipid metabolism, P2Y12-R has been found to trigger HDL transcytosis through endothelial cells, a process known to be protective against lipid deposition in the vascular wall. Better characterization of the role of purinergic P2Y-R and downstream signaling pathways in determination of the endothelial cell phenotype in healthy and pathological environments has clinical potential for the prevention and treatment of cardiovascular diseases.

Discussion

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Cite This Study

Cabou et al. (2022) conducted a review in Cardiovascular disease, atherosclerosis, and vascular remodeling. Endothelial purinergic P2Y receptors (P2Y1-R, P2Y2-R, P2Y12-R) was evaluated.

synapsesocial.com/papers/6a74a7e54b0395c886dbda09 https://doi.org/10.3390/ijms23115883

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The Interplay of Endothelial P2Y Receptors in Cardiovascular Health: From Vascular Physiology to Pathology

Figures

Key Points

Structured PICO

Limitations

Implication

Abstract

Discussion

Cite This Study

The Interplay of Endothelial P2Y Receptors in Cardiovascular Health: From Vascular Physiology to Pathology

Figures

Key Points

Structured PICO

Limitations

Implication

Abstract

Discussion

Cite This Study

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