Details for: NOS3

Gene ID: 4846

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: NOS3

Ensembl ID: ENSG00000164867

Description: nitric oxide synthase 3

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • cardiac endothelial cell CL0010008
    CSI 2.66
    rCSI 10.72%
    PRS 91.37
  • endothelial cell of periportal hepatic sinusoid CL0019021
    CSI 2.59
    rCSI 11.89%
    PRS 92.59
  • ependymal cell CL0000065
    CSI 2.4
    rCSI 4.88%
    PRS 73.99
  • blood vessel endothelial cell CL0000071
    CSI 2.2
    rCSI 4.57%
    PRS 89.35
  • cerebral cortex endothelial cell CL1001602
    CSI 2.19
    rCSI 3.78%
    PRS 85.77
  • retinal blood vessel endothelial cell CL0002585
    CSI 1.68
    rCSI 2.69%
    PRS 93.04
  • endothelial cell of pericentral hepatic sinusoid CL0019022
    CSI 1.67
    rCSI 5.14%
    PRS 92.45
  • endocardial cell CL0002350
    CSI 1.44
    rCSI 6.91%
    PRS 87.34
  • pulmonary artery endothelial cell CL1001568
    CSI 1.29
    rCSI 1.76%
    PRS 94.98
  • endothelial cell of arteriole CL1000412
    CSI 1.28
    rCSI 7.1%
    PRS 95.82
  • type EC enteroendocrine cell CL0000577
    CSI 0.96
    rCSI 3.4%
    PRS 92.16

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

Comma-separated if multiple.
Comma-separated if multiple.
Legend:
  • Query Gene
  • Node Color (Target Cell CSI, relative to current network):
    • Very High
    • High
    • Medium
    • Low
    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [NOS3](/details-gene/4846) (Nitric Oxide Synthase 3), also known as endothelial NOS (eNOS), is a protein-coding gene located on chromosome 7q36.1. It encodes a key enzyme responsible for the synthesis of nitric oxide (NO), a critical signaling molecule involved in numerous physiological processes. Initial characterization and cloning of this gene were reported in the early 1990s ([Link](https://doi.org/10.1016/s0021-9258(18)42066-2), [Link](https://doi.org/10.1016/0014-5793(92)80697-f)). Functionally, [NOS3](/details-gene/4846) plays a central role in cardiovascular homeostasis, primarily through regulating vascular tone (vasodilation), as well as participating in angiogenesis, platelet activation, and cellular responses to mechanical stimuli. Its expression is most significant in various endothelial cell populations, underscoring its role as a master regulator of vascular biology. Dysregulation of [NOS3](/details-gene/4846) is associated with several cardiovascular pathologies, including hypertension ([163729](https://omim.org/entry/163729)). ## Cellular Roles and Expression Landscape **Overall**, the expression profile of [NOS3](/details-gene/4846) firmly establishes it as a cornerstone gene of the vascular endothelium. It exhibits the highest significance scores across a wide array of endothelial cell subtypes. These include [cardiac endothelial cells](/details-cell/CL0010008) (CSI: 2.66), [endothelial cells of periportal hepatic sinusoids](/details-cell/CL0019021) (CSI: 2.59), and general [blood vessel endothelial cells](/details-cell/CL0000071) (CSI: 2.20). Its high significance is also noted in specialized endothelia such as those in the brain ([cerebral cortex endothelial cell](/details-cell/CL1001602)) and retina ([retinal blood vessel endothelial cell](/details-cell/CL0002585)), suggesting a conserved and vital function in maintaining vascular health across different organs. Beyond the endothelium, [NOS3](/details-gene/4846) shows significant expression in [ependymal cells](/details-cell/CL0000065) (CSI: 2.40), the epithelial-like cells lining the cerebral ventricles, which may indicate a role in regulating cerebrospinal fluid dynamics or neuronal function. A moderate signal in [type EC enteroendocrine cells](/details-cell/CL0000577) suggests a potential, albeit less characterized, role in gastrointestinal signaling. The collective data highlight [NOS3](/details-gene/4846) as a definitive marker and functional workhorse of endothelial lineages, critical for organ-specific vascular control. ## Pathways and Molecular Function The molecular function of [NOS3](/details-gene/4846) is centered on its `Nitric-oxide synthase activity` ([GO:0004517](https://www.ebi.ac.uk/QuickGO/term/GO:0004517)), which catalyzes the production of nitric oxide from L-arginine. This activity requires several cofactors, including flavin adenine dinucleotide ([GO:0050660](https://www.ebi.ac.uk/QuickGO/term/GO:0050660)), heme ([GO:0020037](https://www.ebi.ac.uk/QuickGO/term/GO:0020037)), and tetrahydrobiopterin ([GO:0034617](https://www.ebi.ac.uk/QuickGO/term/GO:0034617)). The synthesized nitric oxide then participates in `Nitric oxide mediated signal transduction` ([GO:0007263](https://www.ebi.ac.uk/QuickGO/term/GO:0007263)), primarily by activating soluble guanylate cyclase, as detailed in the Reactome pathway `Nitric oxide stimulates guanylate cyclase` ([R-HSA-392154](https://reactome.org/content/detail/R-HSA-392154)). This core function supports a broad range of biological processes consistent with its endothelial expression. These include `Vasodilation` ([GO:0042311](https://www.ebi.ac.uk/QuickGO/term/GO:0042311)), `Negative regulation of blood pressure` ([GO:0045776](https://www.ebi.ac.uk/QuickGO/term/GO:0045776)), and `Negative regulation of platelet activation` ([GO:0010544](https://www.ebi.ac.uk/QuickGO/term/GO:0010544)), which are all integral to `Hemostasis` ([R-HSA-109582](https://reactome.org/content/detail/R-HSA-109582)). Furthermore, [NOS3](/details-gene/4846) is a critical component of pathways governing vascular development and remodeling, such as `Angiogenesis` ([GO:0001525](https://www.ebi.ac.uk/QuickGO/term/GO:0001525)) and the `Vegfa-vegfr2 pathway` ([R-HSA-4420097](https://reactome.org/content/detail/R-HSA-4420097)). Its involvement in `Response to fluid shear stress` ([GO:0034405](https://www.ebi.ac.uk/QuickGO/term/GO:0034405)) and `Cellular responses to mechanical stimuli` ([R-HSA-9855142](https://reactome.org/content/detail/R-HSA-9855142)) highlights its role as a transducer of mechanical forces into biochemical signals within the vasculature. ## Research Directions The central role of [NOS3](/details-gene/4846) in vascular homeostasis makes its dysregulation a key factor in pathology, particularly in cardiovascular and neoplastic diseases. **Proposed Hypotheses:** 1. Given its critical function in regulating vascular tone, it is hypothesized that specific single-nucleotide polymorphisms (SNPs) within the [NOS3](/details-gene/4846) gene or its regulatory regions impair its enzymatic activity or expression in [blood vessel endothelial cells](/details-cell/CL0000071), leading to endothelial dysfunction and contributing to the genetic risk for essential hypertension. 2. Based on its involvement in `Positive regulation of angiogenesis` ([GO:0045766](https://www.ebi.ac.uk/QuickGO/term/GO:0045766)), it is hypothesized that the tumor microenvironment promotes the upregulation and sustained activation of [NOS3](/details-gene/4846) in tumor-associated endothelial cells, thereby driving neovascularization and facilitating tumor growth and metastasis. **Experimental Approach:** To test the second hypothesis, an endothelial-specific conditional knockout mouse model could be employed. `Nos3 flox/flox` mice could be crossed with mice expressing Cre recombinase under an endothelial-specific promoter (e.g., Cdh5-CreERT2). Following tumor implantation (e.g., Lewis lung carcinoma or B16 melanoma), Cre-mediated deletion of `Nos3` would be induced in the tumor-bearing mice. The impact of endothelial `Nos3` deletion on tumor growth rate, tumor vessel density (via CD31 immunohistochemistry), and vessel perfusion could then be quantified and compared to control animals. This experiment would directly assess the necessity of endothelial [NOS3](/details-gene/4846) for tumor angiogenesis *in vivo*. **Therapeutic Potential:** [NOS3](/details-gene/4846) represents a complex but promising therapeutic target with context-dependent strategies. * **Activation/Enhancement:** In diseases characterized by endothelial dysfunction, such as atherosclerosis, hypertension, and ischemia-reperfusion injury, strategies to enhance [NOS3](/details-gene/4846) activity would be beneficial. This could involve small molecules that allosterically activate the enzyme or supplementation with its essential cofactor, tetrahydrobiopterin (BH4). * **Inhibition:** Conversely, in the context of cancer, where angiogenesis is pathological, selective inhibition of [NOS3](/details-gene/4846) within the tumor vasculature could serve as an effective anti-angiogenic therapy. Developing inhibitors that specifically target [NOS3](/details-gene/4846) over other NOS isoforms would be critical to minimize systemic side effects, such as hypertension.

Genular Protein ID: 2770121937

Symbol: NOS3_HUMAN

Name: Constitutive NOS

UniProtKB Accession Codes:

P29474 A0S0A7 A0S0A8 A8KA63 B2RCQ1 E9PFR2 Q13662 Q14251 Q14434 Q548C1 Q6GSL5 Q9UDC6

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 BMRB 1 BRENDA 1 Bgee 1 BindingDB 1 BioCyc 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 3 CDD 1 CORUM 1 CTD 1 ChEBI 55 ChEMBL 1 ChiTaRS 1 DIP 1 DMDM 1 DNASU 1 DisGeNET 1 DrugBank 43 DrugCentral 1 EC 1 EMBL 49 Ensembl 3 EvolutionaryTrace 1 ExpressionAtlas 1 GO 67 Gene3D 4 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyCosmos 1 GlyGen 1 GuidetoPHARMACOLOGY 1 HGNC 1 HPA 1 InParanoid 1 IntAct 1 InterPro 17 KEGG 1 MANE-Select 1 MIM 1 MINT 1 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PDB 69 PDBsum 69 PIR 1 PIRSF 1 PRINTS 2 PRO 1 PROSITE 3 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 4 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 3 RNAct 1 Reactome 8 RefSeq 5 Rhea 2 SIGNOR 1 SMR 1 STRING 1 SUPFAM 4 SignaLink 1 SwissPalm 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 1378832

Title: Cloning and expression of a cDNA encoding human endothelium-derived relaxing factor/nitric oxide synthase.

PubMed ID: 1378832

DOI: 10.1016/s0021-9258(18)42066-2

PubMed ID: 1379542

Title: Molecular cloning and characterization of human endothelial nitric oxide synthase.

PubMed ID: 1379542

DOI: 10.1016/0014-5793(92)80697-f

PubMed ID: 7688726

Title: Structure and chromosomal localization of the human constitutive endothelial nitric oxide synthase gene.

PubMed ID: 7688726

DOI: 10.1016/s0021-9258(19)85359-0

PubMed ID: 7509596

Title: Gene structure, polymorphism and mapping of the human endothelial nitric oxide synthase gene.

PubMed ID: 7509596

DOI: 10.1006/bbrc.1994.1146

PubMed ID: 7519987

Title: Cloning and structural characterization of the human endothelial nitric-oxide-synthase gene.

PubMed ID: 7519987

DOI: 10.1111/j.1432-1033.1994.tb19045.x

PubMed ID: 17264164

Title: Alternative splicing in intron 13 of the human eNOS gene: a potential mechanism for regulating eNOS activity.

PubMed ID: 17264164

DOI: 10.1096/fj.06-7434com

PubMed ID: 14702039

Title: Complete sequencing and characterization of 21,243 full-length human cDNAs.

PubMed ID: 14702039

DOI: 10.1038/ng1285

PubMed ID: 12853948

Title: The DNA sequence of human chromosome 7.

PubMed ID: 12853948

DOI: 10.1038/nature01782

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 7514568

Title: Isolation and chromosomal localization of the human endothelial nitric oxide synthase (NOS3) gene.

PubMed ID: 7514568

DOI: 10.1006/geno.1994.1068

PubMed ID: 7475956

Title: Expression of constitutive endothelial nitric oxide synthase in human blood platelets.

PubMed ID: 7475956

DOI: 10.1016/0024-3205(95)02191-k

PubMed ID: 7515611

Title: Purification and characterization of the constitutive nitric oxide synthase from human placenta.

PubMed ID: 7515611

DOI: 10.1006/abbi.1994.1232

PubMed ID: 11149895

Title: NOSIP, a novel modulator of endothelial nitric oxide synthase activity.

PubMed ID: 11149895

DOI: 10.1096/fj.00-0078com

PubMed ID: 12446846

Title: NOSTRIN: a protein modulating nitric oxide release and subcellular distribution of endothelial nitric oxide synthase.

PubMed ID: 12446846

DOI: 10.1073/pnas.252345399

PubMed ID: 16126727

Title: Endothelial thrombomodulin induces Ca2+ signals and nitric oxide synthesis through epidermal growth factor receptor kinase and calmodulin kinase II.

PubMed ID: 16126727

DOI: 10.1074/jbc.m506374200

PubMed ID: 16234328

Title: NOSTRIN functions as a homotrimeric adaptor protein facilitating internalization of eNOS.

PubMed ID: 16234328

DOI: 10.1242/jcs.02620

PubMed ID: 16135813

Title: Cell cycle-regulated inactivation of endothelial NO synthase through NOSIP-dependent targeting to the cytoskeleton.

PubMed ID: 16135813

DOI: 10.1128/mcb.25.18.8251-8258.2005

PubMed ID: 20213743

Title: CDK5 phosphorylates eNOS at Ser-113 and regulates NO production.

PubMed ID: 20213743

DOI: 10.1002/jcb.22515

PubMed ID: 23585225

Title: LPS induces pp60c-src-mediated tyrosine phosphorylation of Hsp90 in lung vascular endothelial cells and mouse lung.

PubMed ID: 23585225

DOI: 10.1152/ajplung.00419.2012

PubMed ID: 23186163

Title: Toward a comprehensive characterization of a human cancer cell phosphoproteome.

PubMed ID: 23186163

DOI: 10.1021/pr300630k

PubMed ID: 24275569

Title: An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome.

PubMed ID: 24275569

DOI: 10.1016/j.jprot.2013.11.014

PubMed ID: 35772285

Title: 2-Aminopyridines with a shortened amino sidechain as potent, selective, and highly permeable human neuronal nitric oxide synthase inhibitors.

PubMed ID: 35772285

DOI: 10.1016/j.bmc.2022.116878

PubMed ID: 10074942

Title: Structural characterization of nitric oxide synthase isoforms reveals striking active-site conservation.

PubMed ID: 10074942

DOI: 10.1038/6675

PubMed ID: 12437348

Title: Conformational changes in nitric oxide synthases induced by chlorzoxazone and nitroindazoles: crystallographic and computational analyses of inhibitor potency.

PubMed ID: 12437348

DOI: 10.1021/bi026313j

PubMed ID: 18849972

Title: Anchored plasticity opens doors for selective inhibitor design in nitric oxide synthase.

PubMed ID: 18849972

DOI: 10.1038/nchembio.115

PubMed ID: 25286850

Title: Structures of human constitutive nitric oxide synthases.

PubMed ID: 25286850

DOI: 10.1107/s1399004714017064

PubMed ID: 9737779

Title: A missense Glu298Asp variant in the endothelial nitric oxide synthase gene is associated with coronary spasm in the Japanese.

PubMed ID: 9737779

DOI: 10.1007/s004390050785

PubMed ID: 11740345

Title: In-vivo effects of Glu298Asp endothelial nitric oxide synthase polymorphism.

PubMed ID: 11740345

DOI: 10.1097/00008571-200112000-00009

PubMed ID: 16959974

Title: The consensus coding sequences of human breast and colorectal cancers.

PubMed ID: 16959974

DOI: 10.1126/science.1133427

Sequence Information:

  • Length: 1203
  • Mass: 133275
  • Checksum: B761A6D40B1A5649
  • Sequence:
    • MGNLKSVAQE PGPPCGLGLG LGLGLCGKQG PATPAPEPSR APASLLPPAP EHSPPSSPLT 
QPPEGPKFPR VKNWEVGSIT YDTLSAQAQQ DGPCTPRRCL GSLVFPRKLQ GRPSPGPPAP 
EQLLSQARDF INQYYSSIKR SGSQAHEQRL QEVEAEVAAT GTYQLRESEL VFGAKQAWRN 
APRCVGRIQW GKLQVFDARD CRSAQEMFTY ICNHIKYATN RGNLRSAITV FPQRCPGRGD 
FRIWNSQLVR YAGYRQQDGS VRGDPANVEI TELCIQHGWT PGNGRFDVLP LLLQAPDDPP 
ELFLLPPELV LEVPLEHPTL EWFAALGLRW YALPAVSNML LEIGGLEFPA APFSGWYMST 
EIGTRNLCDP HRYNILEDVA VCMDLDTRTT SSLWKDKAAV EINVAVLHSY QLAKVTIVDH 
HAATASFMKH LENEQKARGG CPADWAWIVP PISGSLTPVF HQEMVNYFLS PAFRYQPDPW 
KGSAAKGTGI TRKKTFKEVA NAVKISASLM GTVMAKRVKA TILYGSETGR AQSYAQQLGR 
LFRKAFDPRV LCMDEYDVVS LEHETLVLVV TSTFGNGDPP ENGESFAAAL MEMSGPYNSS 
PRPEQHKSYK IRFNSISCSD PLVSSWRRKR KESSNTDSAG ALGTLRFCVF GLGSRAYPHF 
CAFARAVDTR LEELGGERLL QLGQGDELCG QEEAFRGWAQ AAFQAACETF CVGEDAKAAA 
RDIFSPKRSW KRQRYRLSAQ AEGLQLLPGL IHVHRRKMFQ ATIRSVENLQ SSKSTRATIL 
VRLDTGGQEG LQYQPGDHIG VCPPNRPGLV EALLSRVEDP PAPTEPVAVE QLEKGSPGGP 
PPGWVRDPRL PPCTLRQALT FFLDITSPPS PQLLRLLSTL AEEPREQQEL EALSQDPRRY 
EEWKWFRCPT LLEVLEQFPS VALPAPLLLT QLPLLQPRYY SVSSAPSTHP GEIHLTVAVL 
AYRTQDGLGP LHYGVCSTWL SQLKPGDPVP CFIRGAPSFR LPPDPSLPCI LVGPGTGIAP 
FRGFWQERLH DIESKGLQPT PMTLVFGCRC SQLDHLYRDE VQNAQQRGVF GRVLTAFSRE 
PDNPKTYVQD ILRTELAAEV HRVLCLERGH MFVCGDVTMA TNVLQTVQRI LATEGDMELD 
EAGDVIGVLR DQQRYHEDIF GLTLRTQEVT SRIRTQSFSL QERQLRGAVP WAFDPPGSDT 
NSP

Genular Protein ID: 267244175

Symbol: A0S0A6_HUMAN

Name: N/A

UniProtKB Accession Codes:

A0S0A6

Database IDs:

ARBA 12 AlphaFoldDB 1 BioGRID-ORCS 1 CDD 1 CTD 1 ChEBI 12 DNASU 1 DisGeNET 1 EC 1 EMBL 2 GO 4 Gene3D 2 InterPro 9 NCBI Taxonomy 1 OrthoDB 1 PANTHER 2 PRINTS 1 PROSITE 3 PeptideAtlas 1 Pfam 2 PharmGKB 1 RefSeq 1 Rhea 2 SAM 1 SMR 1 SUPFAM 2

Citations:

PubMed ID: 17264164

Title: Alternative splicing in intron 13 of the human eNOS gene: a potential mechanism for regulating eNOS activity.

PubMed ID: 17264164

DOI: 10.1096/fj.06-7434com

Sequence Information:

  • Length: 596
  • Mass: 65584
  • Checksum: 8503AC7A8B4E9C06
  • Sequence:
    • MGNLKSVAQE PGPPCGLGLG LGLGLCGKQG PATPAPEPSR APASLLPPAP EHSPPSSPLT 
QPPEGPKFPR VKNWEVGSIT YDTLSAQAQQ DGPCTPRRCL GSLVFPRKLQ GRPSPGPPAP 
EQLLSQARDF INQYYSSIKR SGSQAHEQRL QEVEAEVAAT GTYQLRESEL VFGAKQAWRN 
APRCVGRIQW GKLQVFDARD CRSAQEMFTY ICNHIKYATN RGNLRSAITV FPQRCPGRGD 
FRIWNSQLVR YAGYRQQDGS VRGDPANVEI TELCIQHGWT PGNGRFDVLP LLLQAPDEPP 
ELFLLPPELV LEVPLEHPTL EWFAALGLRW YALPAVSNML LEIGGLEFPA APFSGWYMST 
EIGTRNLCDP HRYNILEDVA VCMDLDTRTT SSLWKDKAAV EINVAVLHSY QLAKVTIVDH 
HAATASFMKH LENEQKARGG CPADWAWIVP PISGSLTPVF HQEMVNYFLS PAFRYQPDPW 
KGSAAKGTGI TRKKTFKEVA NAVKISASLM GTVMAKRVKA TILYGSETGR AQSYAQQLGR 
LFRKAFDPRV LCMDEYDVVS LEHETLVLVV TSTFGNGDPP ENGESVSLPE VSVTTE