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Natriuretic Peptide Receptor 2 Locus Contributes to Carotid Remodeling.

ABSTRACT: Background Carotid artery intima/media thickness (IMT) is a hallmark trait associated with future cardiovascular events. The goal of this study was to map new genes that regulate carotid IMT by genome-wide association. Methods and Results We induced IMT by ligation procedure of the left carotid artery in 30 inbred mouse strains. Histologic reconstruction revealed significant variation in left carotid artery intima, media, adventitia, external elastic lamina volumes, intima-to-media ratio, and (intima+media)/external elastic lamina percent ratio in inbred mice. The carotid remodeling trait was regulated by distinct genomic signatures with a dozen common single-nucleotide polymorphisms associated with left carotid artery intima volume, intima-to-media ratio, and (intima+media)/external elastic lamina percent ratio. Among genetic loci on mouse chromosomes 1, 4, and 12, there was natriuretic peptide receptor 2 (Npr2), a strong candidate gene. We observed that only male, not female, mice heterozygous for a targeted Npr2 deletion (Npr2+/-) exhibited defective carotid artery remodeling compared with Npr2 wild-type (Npr2+/+) littermates. Fibrosis in carotid IMT was significantly increased in Npr2+/- males compared with Npr2+/- females or Npr2+/+ mice. We also detected decreased Npr2 expression in human atherosclerotic plaques, similar to that seen in studies in Npr2+/- mice. Conclusions We found that components of carotid IMT were regulated by distinct genetic factors. We also showed a critical role for Npr2 in genetic regulation of vascular fibrosis associated with defective carotid remodeling.

SUBMITTER: Korshunov VA

PROVIDER: S-EPMC7660849 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Natriuretic Peptide Receptor 2 Locus Contributes to Carotid Remodeling.

Korshunov Vyacheslav A VA Smolock Elaine M EM Wines-Samuelson Mary E ME Faiyaz Abrar A Mickelsen Deanne M DM Quinn Breandan B Pan Calvin C Dugbartey George J GJ Yan Chen C Doyley Marvin M MM Lusis Aldons J AJ Berk Bradford C BC

Journal of the American Heart Association 20200512 10

Background Carotid artery intima/media thickness (IMT) is a hallmark trait associated with future cardiovascular events. The goal of this study was to map new genes that regulate carotid IMT by genome-wide association. Methods and Results We induced IMT by ligation procedure of the left carotid artery in 30 inbred mouse strains. Histologic reconstruction revealed significant variation in left carotid artery intima, media, adventitia, external elastic lamina volumes, intima-to-media ratio, and (i ...[more]

PMID: 32394795

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Project description:BackgroundAngiogenesis and vascular remodeling are complementary, innate responses to ischemic cardiovascular events, including peripheral artery disease and myocardial infarction, which restore tissue blood supply and oxygenation; the endothelium plays a critical function in these intrinsic protective processes. C-type natriuretic peptide (CNP) is a fundamental endothelial signaling species that coordinates vascular homeostasis. Herein, we sought to delineate a central role for CNP in angiogenesis and vascular remodeling in response to ischemia.MethodsThe in vitro angiogenic capacity of CNP was examined in pulmonary microvascular endothelial cells and aortic rings isolated from wild-type, endothelium-specific CNP-/-, global natriuretic peptide receptor (NPR)-B-/- and NPR-C-/- animals, and human umbilical vein endothelial cells. These studies were complemented by in vivo investigation of neovascularization and vascular remodeling after ischemia or vessel injury, and CNP/NPR-C expression and localization in tissue from patients with peripheral artery disease.ResultsClinical vascular ischemia is associated with reduced levels of CNP and its cognate NPR-C. Moreover, genetic or pharmacological inhibition of CNP and NPR-C, but not NPR-B, reduces the angiogenic potential of pulmonary microvascular endothelial cells, human umbilical vein endothelial cells, and isolated vessels ex vivo. Angiogenesis and remodeling are impaired in vivo in endothelium-specific CNP-/- and NPR-C-/-, but not NPR-B-/-, mice; the detrimental phenotype caused by genetic deletion of endothelial CNP, but not NPR-C, can be rescued by pharmacological administration of CNP. The proangiogenic effect of CNP/NPR-C is dependent on activation of Gi, ERK1/2, and phosphoinositide 3-kinase γ/Akt at a molecular level.ConclusionsThese data define a central (patho)physiological role for CNP in angiogenesis and vascular remodeling in response to ischemia and provide the rationale for pharmacological activation of NPR-C as an innovative approach to treating peripheral artery disease and ischemic cardiovascular disorders.

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Natriuretic Peptide Receptor 2 Locus Contributes to Carotid Remodeling.

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Natriuretic Peptide Receptor 2 Locus Contributes to Carotid Remodeling.

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