Elastin insufficiency predisposes to elevated pulmonary circulatory pressures through changes in elastic artery structure.
Elastin is a major structural component of large elastic arteries and a principal determinant of arterial biomechanical properties. Elastin loss-of-function mutations in humans have been linked to the autosomal-dominant disease supravalvular aortic stenosis, which is characterized by stenotic lesions in both the systemic and pulmonary circulations. To better understand how elastin insufficiency influences the pulmonary circulation, we evaluated pulmonary cardiovascular physiology in a unique set of transgenic and knockout mice with graded vascular elastin dosage (range 45-120% of wild type). The central pulmonary arteries of elastin-insufficient mice had smaller internal diameters (P < 0.0001), thinner walls (P = 0.002), and increased opening angles (P = 0.002) compared with wild-type controls. Pulmonary circulatory pressures, measured by right ventricular catheterization, were significantly elevated in elastin-insufficient mice (P < 0.0001) and showed an inverse correlation with elastin level. Although elastin-insufficient animals exhibited mild to moderate right ventricular hypertrophy (P = 0.0001) and intrapulmonary vascular remodeling, the changes were less than expected, given the high right ventricular pressures, and were attenuated compared with those seen in hypoxia-induced models of pulmonary arterial hypertension. The absence of extensive pathological cardiac remodeling at the high pressures in these animals suggests a developmental adaptation designed to maintain right-sided cardiac output in a vascular system with altered elastin content.
Shifren
Adrian
A
Department of Internal Medicine, Washington University School of Medicine, 660 S. Euclid, St. Louis, MO 63110, USA. ashifren@cellbiology.wustl.edu
Durmowicz
Anthony G
AG
Knutsen
Russell H
RH
Faury
Gilles
G
Mecham
Robert P
RP
D000222:Adaptation, Physiological; D000818:Animals; D001794:Blood Pressure; D004549:Elastin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006976:Hypertension, Pulmonary / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D017380:Hypertrophy, Right Ventricular / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011651:Pulmonary Artery / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D011652:Pulmonary Circulation; D013314:Stress, Mechanical; D016278:Ventricular Function, Right; D017725:Ventricular Pressure
D004549:Elastin
J Physiol. 2003 Oct 1;552(Pt 1):185-95
12844513
Arterioscler Thromb Vasc Biol. 2005 May;25(5):932-43
15731494
J Clin Invest. 1998 Jun 1;101(11):2468-77
9616218
J Clin Invest. 2003 Nov;112(9):1419-28
14597767
Pediatr Pathol. 1994 Jan-Feb;14(1):61-8
8159621
FASEB J. 1993 Oct;7(13):1208-18
8405806
Circulation. 2007 Mar 13;115(10):1275-84
17339547
J Clin Invest. 2003 May;111(10):1519-27
12750401
J Clin Invest. 1998 Nov 15;102(10):1783-7
9819363
Circ Res. 2005 Sep 16;97(6):596-604
16109920
Hum Genet. 2000 Jun;106(6):577-88
10942104
Pediatr Rev. 1999 Nov;20(11):e91-e102
10551895
J Biomech Eng. 2004 Apr;126(2):309-14
15179864
Lab Invest. 1988 Nov;59(5):702-9
3184869
Am J Physiol. 1991 Dec;261(6 Pt 2):H1716-26
1836309
J Appl Physiol (1985). 1991 Jun;70(6):2455-70
1885439
Circulation. 2005 Feb 8;111(5):607-13
15699281
Circ Res. 2008 Feb 15;102(3):380-8
18079409
Am J Physiol. 1999 Nov;277(5):H1745-53
10564127
Br Heart J. 1969 May;31(3):375-85
5401816
J Clin Invest. 2008 May;118(5):1606-15
18452001
Circulation. 2007 Mar 13;115(10):1260-8
17309917
J Biomech. 1979;12(9):651-5
489633
Cardiol Young. 1999 Jul;9(4):364-70
10476825
Circulation. 2004 Oct 26;110(17):2609-17
15492299
Am J Physiol Heart Circ Physiol. 2005 Sep;289(3):H1209-17
15863465
J Biomech Eng. 1996 Feb;118(1):62-73
8833076
Cardiovasc Intervent Radiol. 2007 Jul-Aug;30(4):782-5
17401760
Circulation. 2005 Feb 8;111(5):534-8
15699271
Am J Physiol Heart Circ Physiol. 2002 Dec;283(6):H2268-75
12388247
Am J Physiol Lung Cell Mol Physiol. 2005 Dec;289(6):L1083-93
16085670
Circulation. 2006 Feb 7;113(5):601-3
16461830
Pediatr Pulmonol. 2005 Jun;39(6):492-503
15789439
Circ Res. 2006 Sep 29;99(7):675-91
17008597
Eur Heart J. 1993 Nov;14(11):1458-64
8299625
Annu Rev Physiol. 1997;59:89-144
9074758
J Am Soc Echocardiogr. 2006 Apr;19(4):403-12
16581479
J Biol Chem. 1995 Jul 28;270(30):17778-83
7629078
J Appl Physiol (1985). 1998 Sep;85(3):867-73
9729559
J Am Coll Cardiol. 2006 Feb 21;47(4):799-803
16487848
J Biomech Eng. 1986 May;108(2):189-92
3079517
J Clin Invest. 2000 Jun;105(11):1555-62
10841514
Annu Rev Biomed Eng. 2003;5:413-39
12730083
Am J Physiol Lung Cell Mol Physiol. 2007 Mar;292(3):L778-87
17142349
J Exp Biol. 1999 Dec;202(Pt 23):3305-13
10562513
Circ Res. 2007 Aug 31;101(5):523-31
17626896
J Am Coll Cardiol. 1990 Jun;15(7):1625-30
2345244
Circulation. 2003 Jun 10;107(22):2864-9
12796414
Science. 1987 Jul 24;237(4813):423-6
3603030
Circulation. 2002 Jan 29;105(4):516-21
11815437