Arterial Stiffening with Ultrafast Ultrasound Imaging Gives New Insight into Arterial Phenotype of Vascular Ehlers-Danlos Mouse Models

Guillaume Goudot; Clément Papadacci; Blandine Dizier; Véronique Baudrie; Irmine Ferreira; Catherine Boisson-Vidal; Mickaël Tanter; Xavier Jeunemaître; Mathieu Pernot; Emmanuel Messas; Tristan Mirault

doi:10.1055/a-0599-0841

Ultraschall in der Medizin - European Journal of Ultrasound, Table of Contents

Ultraschall Med 2019; 40(06): 734-742
DOI: 10.1055/a-0599-0841

Original Article

Arterial Stiffening with Ultrafast Ultrasound Imaging Gives New Insight into Arterial Phenotype of Vascular Ehlers-Danlos Mouse Models

Arterielle Steifigkeit mittels Ultrafast-US-Imaging gibt neuen Einblick in den arteriellen Phänotyp von vaskulären Ehlers-Danlos-Mausmodellen

Guillaume Goudot

¹Institut Langevin, INSERM U979, CNRS UMR 7587, ESPCI Paris, PSL Research University, Paris France

³USPC Sorbonne Paris Cité, Paris Descartes University, Paris, France

,

Clément Papadacci

¹Institut Langevin, INSERM U979, CNRS UMR 7587, ESPCI Paris, PSL Research University, Paris France

,

Blandine Dizier

²INSERM UMR_S1140, Faculté de Pharmacie, Paris, France

³USPC Sorbonne Paris Cité, Paris Descartes University, Paris, France

,

Véronique Baudrie

³USPC Sorbonne Paris Cité, Paris Descartes University, Paris, France

⁴PARCC, INSERM U970, Paris, France

,

Irmine Ferreira

³USPC Sorbonne Paris Cité, Paris Descartes University, Paris, France

⁴PARCC, INSERM U970, Paris, France

,

Catherine Boisson-Vidal

²INSERM UMR_S1140, Faculté de Pharmacie, Paris, France

³USPC Sorbonne Paris Cité, Paris Descartes University, Paris, France

,

Mickaël Tanter

¹Institut Langevin, INSERM U979, CNRS UMR 7587, ESPCI Paris, PSL Research University, Paris France

,

Xavier Jeunemaître

³USPC Sorbonne Paris Cité, Paris Descartes University, Paris, France

⁴PARCC, INSERM U970, Paris, France

⁵Hôpital Européen Georges-Pompidou, Assistance Publique – Hôpitaux de Paris, France

,

Mathieu Pernot

¹Institut Langevin, INSERM U979, CNRS UMR 7587, ESPCI Paris, PSL Research University, Paris France

,

Emmanuel Messas

³USPC Sorbonne Paris Cité, Paris Descartes University, Paris, France

⁴PARCC, INSERM U970, Paris, France

⁵Hôpital Européen Georges-Pompidou, Assistance Publique – Hôpitaux de Paris, France

,

Tristan Mirault

³USPC Sorbonne Paris Cité, Paris Descartes University, Paris, France

⁴PARCC, INSERM U970, Paris, France

⁵Hôpital Européen Georges-Pompidou, Assistance Publique – Hôpitaux de Paris, France

› Author Affiliations

Abstract

Objective Vascular Ehlers–Danlos syndrome (vEDS) is associated with arterial ruptures due to a mutant gene encoding collagen type III (Col-III). To better understand the role of Col-III, we aimed at evaluating aortic stiffness and dynamic stiffening in vEDS mouse models, with either a quantitative (col3KO mice) or a qualitative Col-III defect (col3KI mice).

Materials and Methods Abdominal aortic wall pulse wave velocities (PWV) in col3KO and col3KI mice were compared to their respective wild type (WT) littermates using a 15 MHz ultrafast ultrasonic transducer. A carotid catheter continuously monitored pressure changes due to phenylephrine injections. PWV1, generated at diastolic blood pressure (DBP), and PWV2, at systolic blood pressure (SBP) were recorded. Difference between PWV2 and PWV1 (Delta-PWV) normalized by the pulse pressure (PP), corresponding to the aortic stiffening over the cardiac cycle, were compared between mutant and WT mice, as well as the regression slope of PWV as a function of pressure.

Results Delta-PWV/PP was lower in col3KO (p = 0.033) and col3KI mice (p < 0.001) vs. WT-mice regardless of the pressure level. The slope of PWV1 with DBP increase showed a lower arterial stiffness in mutant mice vs. controls in both models. This difference was amplified when evaluating stiffness at systolic blood pressure levels with PWV2.

Conclusion In both vEDS mouse models, aortic stiffening was reduced, mainly driven by a lower stiffness at systolic blood pressure. Defective Col-III may be responsible for this, as it is utilized when pressure rises. These pre-clinical data could explain vascular fragility observed in vEDS patients.

Zusammenfassung

Ziel Das vaskuläre Ehlers-Danlos-Syndrom (vEDS) ist mit arteriellen Rupturen assoziiert, zurückzuführen auf ein mutiertes Gen, das für Kollagen Typ III (Col-III) kodiert. Um die Rolle von Col-III besser zu verstehen, untersuchten wir die Aortensteifigkeit und die dynamische Steifigkeit in vEDS-Mausmodellen, die entweder einen quantitativen (col3KO-Mäuse) oder einen qualitativen Col-III-Defekt (col3KI-Mäuse) hatten.

Material und Methoden Die Pulswellengeschwindigkeiten der Bauchaortenwand (PWV) in col3KO- und col3KI-Mäusen wurden mit denen ihrer jeweiligen Wildtyp (WT)- Wurfgeschwister mit einem 15 MHz Ultrafast-Ultraschall-Transducer verglichen. Ein Karotiskatheter überwachte fortlaufend die durch Injektion von Phenylephrin hervorgerufenen Druckänderungen. PWV1, erzeugt bei diastolischem Blutdruck (DBP) und PWV2, bei systolischem Blutdruck (SBP) wurden aufgezeichnet. Der Unterschied zwischen PWV2 und PWV1 (Delta-PWV), normalisiert durch den Pulsdruck (PP), welcher der Aortensteifigkeit beim Herzzyklus entspricht, sowie die Regressionsneigung von PWV als Funktion des Drucks wurde zwischen Mutanten- und WT-Mäusen verglichen.

Ergebnisse Delta-PWV/PP war unabhängig vom Druckniveau niedriger in col3KO- (p = 0,033) und col3KI-Mäusen (p < 0,001) im Vergleich zu WT-Mäusen. Die Neigung von PWV1 bei DBP-Anstieg zeigte bei beiden Modellen eine geringere arterielle Steifigkeit in mutierten Mäusen im Vergleich zu den Kontrollen. Dieser Unterschied wurde verstärkt, wenn die Steifigkeit mit PWV2 bei systolischem Blutdruck bewertet wurde.

Schlussfolgerung Beide vEDS-Mausmodelle hatten eine reduzierte Aortensteifigkeit, hauptsächlich durch die geringere Steifigkeit beim systolischen Blutdruck. Das defekte Col-III Gen könnte dafür verantwortlich sein, da es zum Einsatz kommt, wenn der Druck steigt. Diese präklinischen Daten könnten die bei Patienten mit vEDS beobachtete vaskuläre Fragilität erklären.

Key words

aorta - collagen type III - mouse - pulse wave velocity - arterial stiffness

Full Text

References

References
1 Ong KT, Perdu J, De Backer J. et al. Effect of celiprolol on prevention of cardiovascular events in vascular Ehlers-Danlos syndrome: a prospective randomised, open, blinded-endpoints trial. Lancet (London, England) 2010; 376: 1476-1484
2 Moens AI. Die Pulskurve [The Pulse Curve] (in German). Leiden, The Netherlands: E.J. Brill; 1878
3 Callaghan FJ, Geddes LA, Babbs CF. et al. Relationship between pulse-wave velocity and arterial elasticity. Med Biol Eng Comput 1986; 24: 248-254
4 Boutouyrie P, Germain DP, Fiessinger JN. et al. Increased carotid wall stress in vascular Ehlers-Danlos syndrome. Circulation 2004; 109: 1530-1535
5 Wolinsky H, Glagov S. Structural basis for the static mechanical properties of the aortic media. Circ Res 1964; 14: 400-413
6 Greenwald SE, Moore JE, Rachev A. et al. Experimental investigation of the distribution of residual strains in the artery wall. J Biomech Eng 1997; 119: 438-444
7 Tanter M, Fink M. Ultrafast imaging in biomedical ultrasound. IEEE Trans Ultrason Ferroelectr Freq Control 2014; 61: 102-119
8 Couade M, Pernot M, Messas E. et al. Ultrafast imaging of the arterial pulse wave. Irbm 2011; 32: 106-108
9 Giannattasio C, Salvi P, Valbusa F. et al. Simultaneous Measurement of Beat-to-Beat Carotid Diameter and Pressure Changes to Assess Arterial Mechanical Properties. Hypertension 2008; 52: 896-902
10 Hermeling E, Hoeks APG, Winkens MHM. et al. Noninvasive assessment of arterial stiffness should discriminate between systolic and diastolic pressure ranges. Hypertens (Dallas, Tex 1979) 2010; 55: 124-130
11 Khir AW, O’Brien A, Gibbs JS. et al. Determination of wave speed and wave separation in the arteries. J Biomech 2001; 34: 1145-1155
12 Mirault T, Pernot M, Frank M. et al. Carotid stiffness change over the cardiac cycle by ultrafast ultrasound imaging in healthy volunteers and vascular Ehlers-Danlos syndrome. J Hypertens 2015; 33: 1890-1896 ; discussion 1896
13 Wang YX, Halks-Miller M, Vergona R. et al. Increased aortic stiffness assessed by pulse wave velocity in apolipoprotein E-deficient mice. Am J Physiol Heart Circ Physiol 2000; 278: H428-H434
14 Gotschy A, Bauer E, Schrodt C. et al. Local arterial stiffening assessed by MRI precedes atherosclerotic plaque formation. Circ Cardiovasc Imaging 2013; 6: 916-923
15 Humphrey JD, Eberth JF, Dye WW. et al. Fundamental role of axial stress in compensatory adaptations by arteries. J Biomech 2009; 42: 1-8
16 Leloup AJA, Fransen P, Van Hove CE. et al. Applanation tonometry in mice: a novel noninvasive technique to assess pulse wave velocity and arterial stiffness. Hypertens (Dallas, Tex 1979) 2014; 64: 195-200
17 Frank M, Albuisson J, Ranque B. et al. The type of variants at the COL3A1 gene associates with the phenotype and severity of vascular Ehlers-Danlos syndrome. Eur J Hum Genet 2015; 23: 1657-1664
18 Pepin MG, Schwarze U, Rice KM. et al. Survival is affected by mutation type and molecular mechanism in vascular Ehlers-Danlos syndrome (EDS type IV). Genet Med 2014; 16: 881-888
19 Liu X, Wu H, Byrne M. et al. Type III collagen is crucial for collagen I fibrillogenesis and for normal cardiovascular development. Proc Natl Acad Sci U S A 1997; 94: 1852-1856
20 Cooper TK, Zhong Q, Krawczyk M. et al. The haploinsufficient Col3a1 mouse as a model for vascular Ehlers-Danlos syndrome. Vet Pathol 2010; 47: 1028-1039
21 Fontaine E, Faugeroux J, Beugnon C. et al. Caractérisation d’un modèle murin du Syndrome d’Ehlers-Danlos vasculaire. J Mal Vasc 2015; 40: 119
22 Montaldo G, Tanter M, Bercoff J. et al. Coherent plane-wave compounding for very high frame rate ultrasonography and transient elastography. IEEE Trans Ultrason Ferroelectr Freq Control 2009; 56: 489-506
23 Roach MR, Burton AC. The reason for the shape of the distensibility curves of arteries. Can J Biochem Physiol 1957; 35: 681-690
24 Greenwald SE, Moore JE, Rachev A. et al. Experimental investigation of the distribution of residual strains in the artery wall. J Biomech Eng 1997; 119: 438-444
25 Laurent S. Defining vascular aging and cardiovascular risk. J Hypertens; 2012 30. Suppl: S3–8
26 Paini A, Boutouyrie P, Calvet D. et al. Carotid and aortic stiffness: determinants of discrepancies. Hypertens (Dallas, Tex 1979) 2006; 47: 371-376
27 Verwoert GC, Franco OH, Hoeks APG. et al. Arterial stiffness and hypertension in a large population of untreated individuals: the Rotterdam Study. J Hypertens 2014; 32: 1606-1612 ; discussion 1612
28 Soucy KG, Ryoo S, Benjo A. et al. Impaired shear stress-induced nitric oxide production through decreased NOS phosphorylation contributes to age-related vascular stiffness. J Appl Physiol 2006; 101: 1751-1759
29 Faugeroux J, Nematalla H, Li W. et al. Angiotensin II promotes thoracic aortic dissections and ruptures in Col3a1 haploinsufficient mice. Hypertens (Dallas, Tex 1979) 2013; 62: 203-208

Supplementary Material

Supplementary Material