Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Mar 31;119(2):599-610.
doi: 10.1093/cvr/cvac092.

PHACTR1 modulates vascular compliance but not endothelial function: a translational study

Alice Wood  1   2 , Alexios Antonopoulos  3 , Surawee Chuaiphichai  3   4 , Theodosios Kyriakou  3   4 , Rebeca Diaz  3   4 , Abtehale Al Hussaini  1   2 , Anna-Marie Marsh  1   2 , Manjit Sian  1   2 , Mitul Meisuria  1   2 , Gerry McCann  1   2 , Victoria S Rashbrook  3   4 , Edward Drydale  3   4 , Sally Draycott  3   4 , Murray David Polkinghorne  3 , Ioannis Akoumianakis  3 , Charalambos Antoniades  3 , Hugh Watkins  3   4 , Keith M Channon  3   4 , David Adlam  1   2 , Gillian Douglas  3   4
Affiliations

PHACTR1 modulates vascular compliance but not endothelial function: a translational study

Alice Wood et al. Cardiovasc Res. .

Abstract

Aims: The non-coding locus at 6p24 located in Intron 3 of PHACTR1 has consistently been implicated as a risk allele in myocardial infarction and multiple other vascular diseases. Recent murine studies have identified a role for Phactr1 in the development of atherosclerosis. However, the role of PHACTR1 in vascular tone and in vivo vascular remodelling has yet to be established. The aim of this study was to investigate the role of PHACTR1 in vascular function.

Methods and results: Prospectively recruited coronary artery disease (CAD) patients undergoing bypass surgery and retrospectively recruited spontaneous coronary artery dissection (SCAD) patients and matched healthy volunteers were genotyped at the PHACTR1 rs9349379 locus. We observed a significant association between the PHACTR1 loci and changes in distensibility in both the ascending aorta (AA = 0.0053 ± 0.0004, AG = 0.0041 ± 0.003, GG = 0.0034 ± 0.0009, P < 0.05, n = 58, 54, and 7, respectively) and carotid artery (AA = 12.83 ± 0.51, AG = 11.14 ± 0.38, GG = 11.69 ± 0.66, P < 0.05, n = 70, 65, and 18, respectively). This association was not observed in the descending aorta or in SCAD patients. In contrast, the PHACTR1 locus was not associated with changes in endothelial cell function with no association between the rs9349379 locus and in vivo or ex vivo vascular function observed in CAD patients. This finding was confirmed in our murine model where the loss of Phactr1 on the pro-atherosclerosis ApoE-/- background did not alter ex vivo vascular function.

Conclusion: In conclusion, we have shown a role for PHACTR1 in arterial compliance across multiple vascular beds. Our study suggests that PHACTR1 has a key structural role within the vasculature.

Keywords: PHACTR1; Arteries; Compliance; Endothelial cells.

PubMed Disclaimer

Conflict of interest statement

Conflict of interest: D.A. reports in kind support from Astra Zeneca Inc. for SCAD genetics research and research funding from Astra Zeneca for unrelated research. He has received educational funding from Abbott Vascular Inc. to support a clinical research fellow. He has conducted consultancy for General Electric Inc. to support general research funds. No other authors have any relationships to declare.

Figures

Graphical abstract
Graphical abstract
Figure 1
Figure 1
PHACTR1 coronary artery disease risk allele (GG) did not impact on in vivo vascular function. (A) In vivo dilator response to flow (FMD) was not different across the genotypes (GG; P > 0.05, one-way ANOVA, GG = 102, GA = 189, and AA = 138 subjects per genotype). (B) No difference between genotypes was observed in endothelial cell-independent dilation (EID, GG = 73, GA = 142, and AA = 101 subjects per genotype) in response to GTN in vivo. Population was subdivided into non-hypertensive (no HTN). (C) (G = 66, GA = 147, and AA = 105 subjects per genotype) and (D) (G = 61, GA = 134, AA = 94 subjects per genotype) and hypertensive (E) (G = 76, GA = 139, and AA = 97 subjects per genotype) and (F) (G = 33, GA = 83, and AA = 54 subjects per genotype) no difference was observed in either FMD or EID across the genotypes in either population.
Figure 2
Figure 2
PHACTR1 coronary artery disease risk allele (GG) did not impact on ex vivo vascular function. Endothelial cell-dependent dilation to acetylcholine (A) GG = 33, GA = 83, and AA = 54 subjects per genotype and bradykinin (B) GG = 17, GA = 35, and AA = 19 subjects per genotype was assessed in saphenous veins there was no difference observed across the genotypes (P > 0.05, two-way ANOVA for repeated measures). (C) Endothelial cell-independent dilation in saphenous veins to sodium nitroprusside (SNP, GG = 35, GA = 80, and AA = 51 subjects per genotype) was not different between genotypes.
Figure 3
Figure 3
Carriers of the PHACTR1 coronary artery disease risk allele (GG) had reduced ascending aorta distensibility compared with carriers of the spontaneous coronary artery dissection allele (AA). (A) Ascending aorta distensibility was significantly decreased in carriers of the GG allele compared with carriers of the AA allele P = 0.034: one-way ANOVA. (B) No difference between genotypes was observed in distensibility in the descending aorta (P = 0.317: one-way ANOVA, AA = 58, AG = 54, GG = 7).
Figure 4
Figure 4
Healthy volunteer carriers of the GG allele but not spontaneous coronary artery dissection (SCAD) patients had a reduction in carotid artery distensibility. (A) Carotid artery strain was significantly reduced in carriers of the GG allele in the combined study group (P = 0.027, one-way ANOVA, AA = 70, AG = 65, GG = 18). (B) In SCAD, patient sub-group no difference in strain was observed with genotype (P = 0.19, one-way ANOVA, AA = 55, AG = 47, GG = 11). (C) Healthy volunteers showed a significant reduction in strain with genotype with reduced strain observed in carriers of the GG allele (P = 0.031, one-way ANOVA, AA = 15, AG = 18, GG = 7).
Figure 5
Figure 5
Loss of Phactr1 causes a significant increase in heart rate. (A) Schematic showing the targeting of the murine Phactr1 locus with loxP sites flanking Exon 7, mRNA analysis showing a significant reduction in Phactr1 expression in hearts from Phactr1−/−ApoE−/− mice (P < 0.05, T-Test, adult males, n = 4 Phactr1+/+ApoE−/− and n = 5 Phactr1+/+ApoE−/−). (B) Systolic blood pressure was not significantly different between groups (P > 0.05, T-test). (C) A significant increase in heart rate was observed in Phactr1−/−ApoE−/− mice compared with their Phactr1+/+ApoE−/− control littermates (P < 0.05, T-test). Adult mice between 20 and 22 weeks of age, n = 4 female and 5 male Phactr1+/+ApoE−/− and 3 female and 3 male Phactr1−/−ApoE−/− mice. Data are expressed as the mean ± SEM, each point represents an individual animal. Black bars/symbols = Phactr1+/+, white bars/symbols = Phactr1−/−.
Figure 6
Figure 6
No difference in vasomotor motor function in the aorta of Phactr1−/−ApoE−/− mice. Vasomotor function in the aorta of Phactr1+/+ApoE−/− and Phactr1−/−ApoE−/− was determined using isometric tension studies in a wire myograph. (A) Force of maximal contraction to 45 mmol L−1 KCl. Receptor-mediated vasoconstriction to phenylephrine (PE) expressed in absolute tension (B) and as % of maximum KCL constriction to control for variation in vessel size (C). (D) Vasoconstriction to PE in the presence of NOS inhibitor, L-NAME (100 μmol L−1). Receptor-mediated endothelium-dependent vasodilatation to ACh in the absence (E), presence of L-NAME (F), endothelium-independent vasodilatation to SNP (G). No significant differences were observed between groups (P < 0.05, RM ANOVA); n = 5 male adult (16–19 weeks old) mice per group. Black symbols = Phactr1+/+, white symbols = Phactr1−/−.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Nikpay M, Goel A, Won HH, Hall LM, Willenborg C, Kanoni S, Saleheen D, Kyriakou T, Nelson CP, Hopewell JC, Webb TR, Zeng L, Dehghan A, Alver M, Armasu SM, Auro K, Bjonnes A, Chasman DI, Chen S, Ford I, Franceschini N, Gieger C, Grace C, Gustafsson S, Huang J, Hwang SJ, Kim YK, Kleber ME, Lau KW, Lu X, Lu Y, Lyytikainen LP, Mihailov E, Morrison AC, Pervjakova N, Qu L, Rose LM, Salfati E, Saxena R, Scholz M, Smith AV, Tikkanen E, Uitterlinden A, Yang X, Zhang W, Zhao W, de Andrade M, de Vries PS, van Zuydam NR, Anand SS, Bertram L, Beutner F, Dedoussis G, Frossard P, Gauguier D, Goodall AH, Gottesman O, Haber M, Han BG, Huang J, Jalilzadeh S, Kessler T, Konig IR, Lannfelt L, Lieb W, Lind L, Lindgren CM, Lokki ML, Magnusson PK, Mallick NH, Mehra N, Meitinger T, Memon FU, Morris AP, Nieminen MS, Pedersen NL, Peters A, Rallidis LS, Rasheed A, Samuel M, Shah SH, Sinisalo J, Stirrups KE, Trompet S, Wang L, Zaman KS, Ardissino D, Boerwinkle E, Borecki IB, Bottinger EP, Buring JE, Chambers JC, Collins R, Cupples LA, Danesh J, Demuth I, Elosua R, Epstein SE, Esko T, Feitosa MF, Franco OH, Franzosi MG, Granger CB, Gu D, Gudnason V, Hall AS, Hamsten A, Harris TB, Hazen SL, Hengstenberg C, Hofman A, Ingelsson E, Iribarren C, Jukema JW, Karhunen PJ, Kim BJ, Kooner JS, Kullo IJ, Lehtimaki T, Loos RJ, Melander O, Metspalu A, Marz W, Palmer CN, Perola M, Quertermous T, Rader DJ, Ridker PM, Ripatti S, Roberts R, Salomaa V, Sanghera DK, Schwartz SM, Seedorf U, Stewart AF, Stott DJ, Thiery J, Zalloua PA, O’Donnell CJ, Reilly MP, Assimes TL, Thompson JR, Erdmann J, Clarke R, Watkins H, Kathiresan S, McPherson R, Deloukas P, Schunkert H, Samani NJ, Farrall M, Consortium CAD. A comprehensive 1,000 genomes-based genome-wide association meta-analysis of coronary artery disease. Nat Genet 2015;47:1121–1130. - PMC - PubMed
    1. Howson JMM, Zhao W, Barnes DR, Ho WK, Young R, Paul DS, Waite LL, Freitag DF, Fauman EB, Salfati EL, Sun BB, Eicher JD, Johnson AD, Sheu WHH, Nielsen SF, Lin WY, Surendran P, Malarstig A, Wilk JB, Tybjærg-Hansen A, Rasmussen KL, Kamstrup PR, Deloukas P, Erdmann J, Kathiresan S, Samani NJ, Schunkert H, Watkins H, Do R, Rader DJ, Johnson JA, Hazen SL, Quyyumi AA, Spertus JA, Pepine CJ, Franceschini N, Justice A, Reiner AP, Buyske S, Hindorff LA, Carty CL, North KE, Kooperberg C, Boerwinkle E, Young K, Graff M, Peters U, Absher D, Hsiung CA, Lee WJ, Taylor KD, Chen YH, Lee IT, Guo X, Chung RH, Hung YJ, Rotter JI, Juang JJ, Quertermous T, Wang TD, Rasheed A, Frossard P, Alam DS, Majumder AAS, Di Angelantonio E, Chowdhury R, Chen YI, Nordestgaard BG, Assimes TL, Danesh J, Butterworth AS, Saleheen D. Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms. Nat Genet 2017;49:1113–1119. - PMC - PubMed
    1. Deloukas P, Kanoni S, Willenborg C, Farrall M, Assimes TL, Thompson JR, Ingelsson E, Saleheen D, Erdmann J, Goldstein BA, Stirrups K, König IR, Cazier JB, Johansson A, Hall AS, Lee JY, Willer CJ, Chambers JC, Esko T, Folkersen L, Goel A, Grundberg E, Havulinna AS, Ho WK, Hopewell JC, Eriksson N, Kleber ME, Kristiansson K, Lundmark P, Lyytikäinen LP, Rafelt S, Shungin D, Strawbridge RJ, Thorleifsson G, Tikkanen E, Van Zuydam N, Voight BF, Waite LL, Zhang W, Ziegler A, Absher D, Altshuler D, Balmforth AJ, Barroso I, Braund PS, Burgdorf C, Claudi-Boehm S, Cox D, Dimitriou M, Do R, Doney AS, El Mokhtari N, Eriksson P, Fischer K, Fontanillas P, Franco-Cereceda A, Gigante B, Groop L, Gustafsson S, Hager J, Hallmans G, Han BG, Hunt SE, Kang HM, Illig T, Kessler T, Knowles JW, Kolovou G, Kuusisto J, Langenberg C, Langford C, Leander K, Lokki ML, Lundmark A, McCarthy MI, Meisinger C, Melander O, Mihailov E, Maouche S, Morris AD, Müller-Nurasyid M, Nikus K, Peden JF, Rayner NW, Rasheed A, Rosinger S, Rubin D, Rumpf MP, Schäfer A, Sivananthan M, Song C, Stewart AF, Tan ST, Thorgeirsson G, van der Schoot CE, Wagner PJ, Wells GA, Wild PS, Yang TP, Amouyel P, Arveiler D, Basart H, Boehnke M, Boerwinkle E, Brambilla P, Cambien F, Cupples AL, de Faire U, Dehghan A, Diemert P, Epstein SE, Evans A, Ferrario MM, Ferrières J, Gauguier D, Go AS, Goodall AH, Gudnason V, Hazen SL, Holm H, Iribarren C, Jang Y, Kähönen M, Kee F, Kim HS, Klopp N, Koenig W, Kratzer W, Kuulasmaa K, Laakso M, Laaksonen R, Lee JY, Lind L, Ouwehand WH, Parish S, Park JE, Pedersen NL, Peters A, Quertermous T, Rader DJ, Salomaa V, Schadt E, Shah SH, Sinisalo J, Stark K, Stefansson K, Trégouët DA, Virtamo J, Wallentin L, Wareham N, Zimmermann ME, Nieminen MS, Hengstenberg C, Sandhu MS, Pastinen T, Syvänen AC, Hovingh GK, Dedoussis G, Franks PW, Lehtimäki T, Metspalu A, Zalloua PA, Siegbahn A, Schreiber S, Ripatti S, Blankenberg SS, Perola M, Clarke R, Boehm BO, O’Donnell C, Reilly MP, März W, Collins R, Kathiresan S, Hamsten A, Kooner JS, Thorsteinsdottir U, Danesh J, Palmer CN, Roberts R, Watkins H, Schunkert H, Samani NJ. Large-scale association analysis identifies new risk loci for coronary artery disease. Nat Genet 2013;45:25–33. - PMC - PubMed
    1. Beaudoin M, Gupta RM, Won HH, Lo KS, Do R, Henderson CA, Lavoie-St-Amour C, Langlois S, Rivas D, Lehoux S, Kathiresan S, Tardif JC, Musunuru K, Lettre G. Myocardial infarction-associated SNP at 6p24 interferes with MEF2 binding and associates with PHACTR1 expression levels in human coronary arteries. Arterioscler Thromb Vasc Biol 2015;35:1472–1479. - PMC - PubMed
    1. Ford TJ, Corcoran D, Padmanabhan S, Aman A, Rocchiccioli P, Good R, McEntegart M, Maguire JJ, Watkins S, Eteiba H, Shaukat A, Lindsay M, Robertson K, Hood S, McGeoch R, McDade R, Yii E, Sattar N, Hsu LY, Arai AE, Oldroyd KG, Touyz RM, Davenport AP, Berry C. Genetic dysregulation of endothelin-1 is implicated in coronary microvascular dysfunction. Eur Heart J 2020;41:3239–3252. - PMC - PubMed

Publication types

Substances

Supplementary concepts