Published in Volume
112, Issue 9
(November 1, 2003)J Clin Invest.
Copyright © 2003, American Society for Clinical Investigation
Decreased elastin in vessel walls puts the pressure on
Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York, USA
Address correspondence to: Jeanine D’Armiento, Department of Medicine, Columbia University College of Physicians and Surgeons, Physicians and Surgeons 9-449, 622 West 168th Street, New York, New York 10032, USA. Phone: (212) 305-3745; Fax: (212) 305-5052; E-mail: firstname.lastname@example.org.
Published November 1, 2003
Mice haploinsufficient for elastin develop structural changes in vessel walls similar to those seen in patients with mutations in the elastin gene. A new study demonstrates that due to mechanical changes in the vessel wall, these animals exhibit increased mean arterial pressures. The results evoke the possibility that alterations in elastin may contribute to the development of essential hypertension in patients.
Investigators have understood that the arrangement of the ECM is critical in the formation of organ structures during development and in the remodeling of tissues after injury. However, the ECM is perceived to play a passive role in dynamic pathological processes such as heart failure and hypertension. This misconception largely results from difficulties in interpreting the pathology seen in human diseased tissue without an understanding of the full phenotypic course of the pathologic process over time. The use of transgenic animal studies now allows us to introduce gain of function and loss of function mutations so as to evaluate the direct role of ECM molecules in disease pathogenesis. There are multiple examples of dominant mutations in structural ECM molecules that lead to abnormal tissue formation and disease phenotypes (1). In this issue of the JCI, Faury and colleagues present an interesting example of a dominant mutation in an ECM protein that results in developmental structural changes that ultimately cause the animals to acquire hypertension in their adult life (2).
Elastin and vessel formation
Elastin constitutes 50% of the dry weight of the aorta. During vessel development, elastin synthesized by smooth muscle cells forms elastic fibers that are arranged into concentric rings of elastic lamellae around the arterial lumen. Each elastic lamella alternates with a ring of smooth muscle, forming a lamellar unit. The elastic lamellae allow an artery to comply with the increased hemodynamic stress of cardiac systole and maintain sufficient blood pressure during diastole (Figure 1) (3).
Haploinsufficiency of elastin in mice leads to developmental changes in the vessel wall, resulting in an increase in lamellar units. During the adult life of the animal, these structural changes translate into altered vessel compliance and a significant increase in the mean arterial pressure. These changes are similar to what is observed in two diseases identified as having mutations in the elastin gene; however, the incidence of hypertension (HTN) is lower in the human diseases. These intriguing findings raise the possibility that patients with essential hypertension, who exhibit decreased compliance of their arterial vessels, may have mutations in their elastin gene. Such mutations would lead to structural changes in the vessel during development that predisposes the patients to the development of hypertension later in life.
Variations in the lamellar subunits (defined as the elastic lamellae and adjacent smooth muscle cells) determine the distribution and magnitude of the tensile strength of the vessel. Hence, the greatest number of lamellar units is found in the larger, more proximal vessels that experience higher wall stress, indicating a linear relationship between the number of lamellar units and tensional force within the vessel wall (4, 5).
Elastin mutations in disease
Three clinical conditions have been linked to a mutation or deletion of the elastin gene, ELN. Autosomal dominant cutis laxa, a primarily cutaneous condition, is the result of frameshift mutations in ELN that influence elastic fiber structure through a dominant-negative effect (6). Several years ago, investigators identified mutations in ELN in patients with supravalvular aortic stenosis (SVAS). SVAS is an autosomal dominant disorder caused by intragenic deletions or by a large spectrum of mutations within the elastin gene (7, 8). These result in functional haploinsufficiency through either nonsense-mediated decay of mRNA from the mutant allele or the production of a nonfunctional protein (9, 10). Narrowing of the ascending aorta is a dominant feature of SVAS, but other arteries, including pulmonary arteries, are often also affected. If not corrected, SVAS may lead to cardiac hypertrophy and heart failure (11). Finally, Williams syndrome, a neurodevelopmental disorder that has SVAS as a component, develops as a consequence of submicroscopic deletions within chromosomal subunit 7q11.23 involving the whole of the ELN gene (12).
Alterations in elastin content change arterial wall structure
To directly investigate the consequence of elastin mutations on vessel formation, a mouse with a complete loss of function in the Eln gene was generated (13). The elastin-null mice died of obstructive arterial disease due to subendothelial cell proliferation and reorganization of smooth muscle. These changes occurred in isolated organ cultures of arteries and were not subject to hemodynamic stress (13).
The characterization of mice haploinsufficient for elastin (Eln+/–) revealed a role for elastin in the formation of vessel wall structure (14). The arteries of Eln+/– mice exhibited thinner elastic lamellae and an increased number of smooth muscle cell layers. Most interestingly, these identical changes have been observed in the arteries of patients with SVAS (14).
In the present report, Faury et al. (2) meticulously examined the mechanical properties of the arteries of the Eln+/– mice compared with normal Eln+/+ mice, correlating changes in inner and outer vessel diameter with alterations in transmural pressure. The Eln+/– animals were stably hypertensive with mild cardiac hypertrophy and did not exhibit the hypertension-induced arterial wall hypertrophy and decreased distensibility of large elastic arteries associated with essential hypertension (2). The mean arterial pressure (MAP) of Eln+/– mice could be reduced with angiotensin II inhibitors, and renin levels were two-fold greater than in Eln+/+ mice, suggesting that the renin-angiotensin system plays a role in maintaining the high blood pressure of the Eln+/– mice (2).
The results of this study provide insight into how hemodynamic forces resulting from altered matrix structure influence vascular development (Figure 1). Most importantly, these mutant Eln animals will be extremely useful in identifying the mechanism of hypertension in arteriopathies associated with elastin haploinsufficiency.
Overview and future questions
Vessels of patients with essential hypertension exhibit decreased arterial compliance and increased vascular resistance with an increase in vascular tone (15). Hypertensive patients maintain the decreased compliance at the same pressures as normotensive patients, implying that functional and/or structural changes other than pressure-mediated stretching of arteries contribute toward reducing arterial compliance (16, 17). The discovery of an alteration in vessel compliance in the Eln+/– mice along with increased MAP suggests that vessel elastin in patients with hypertension should be examined. Mutations in the elastin gene could ultimately be a cause of hypertension.
The mechanism by which a change in elastin content leads to alterations in cell signaling and subsequent structural changes in the vessel wall remains to be determined. Matrix molecules bind to integrin receptors, and any alteration in the structural components of the matrix could consequentially alter signaling through the integrin receptors. Additionally, it will be interesting to determine whether elastin loss leads to structural changes in other organs of the Eln+/– mice in response to increased mechanical stress. For example, the lungs from the Eln+/– mice would presumably have diminished elastin content. Since the rodent lung continues to develop until two months after birth, one wonders whether Eln+/– lungs undergo structural reorganization when exposed to postnatal transmural pressure and what the consequences of such reorganization might be on pulmonary function.
Helminen, HJ, Saamanen, AM, Salminen, H, Hyttinen, MM. Transgenic mouse models for studying the role of cartilage macromolecules in osteoarthritis. Rheumatology. 2002. 41:848-856.
Faury, G, et al. Developmental adaptation of the mouse cardiovascular system to elastin haploinsufficiency. J. Clin. Invest. 2003. 112:1419-1428. doi:10.1172/JCI200319028.
Parks, WC, Pierce, RA, Lee, KA, Mecham, RP. Elastin. Advances in Molecular and Cellular Biology. 1993. 6:133-182.
Leung, DYM, Glagov, S, Mathews, MB. Elastin and collagen accumulation in rabbit ascending aorta and pulmonary trunk during postnatal growth: correlation of cellular synthetic response with medial tension. Circ. Res. 1977. 41:316-323.
Clark, JM, Glagov, S. Transmural organization of the arterial media. The lamellar unit revisited. Arteriosclerosis. 1985. 5:19-34.
Tassabehji, M, et al. An elastin gene mutation producing abnormal tropoelastin and abnormal elastic fibres in a patient with autosomal dominant cutis laxa. Hum. Mol. Genet. 1998. 7:1021-1028.
Curran, ME, et al. The elastin gene is disrupted by a translocation associated with supravalvular aortic stenosis. Cell. 1993. 73:159-168.
Ewart, AK, Jin, WS, Atkinson, D, Morris, CA, Keating, MT. Supravalvular aortic stenosis associated with a deletion disrupting the elastin gene. J. Clin. Invest. 1994. 93:1071-1077.
Urban, Z, et al. Supravalvular aortic stenosis: a splice site mutation within the elastin gene results in reduced expression of two aberrantly spliced transcripts. Hum. Genet. 1999. 104:135-142.
Urban, Z, et al. Isolated supravalvular aortic stenosis; functional haploinsufficiency of the elastin gene as a result of nonsense-mediated decay. Hum. Genet. 2000. 106:577-588.
Chowdhury, T, Reardon, W. Elastin mutation and cardiac disease. Pediatr. Cardiol. 1999. 20:103-107.
Lowery, MC, Morris, CA, Ewart, AK. Strong correlation of elastin deletions, detected by FISH, with Williams Syndrome: evaluation of 235 patients. Am. J. Hum. Genet. 1995. 57:49-53.
Li, DY, et al. Elastin is an essential determinant of arterial morphogenesis. Nature. 1998. 393:276-280.
Li, D, et al. Novel arterial pathology in mice and humans hemizygous for elastin. J. Clin. Invest. 1998. 102:1783-1787.
Ting, CT, et al. Arterial hemodynamics in human hypertension. J. Clin. Invest. 1986. 78:1462-1471.
Simon, AC, Levenson, J, Chau, NP, Pithois-Merli, I. Role of arterial compliance in the physiopharmacological approach to human hypertension. J. Cardiovasc. Pharmacol. 1992. 5(Suppl.):S11-S20.
Armentano, R, et al. Mechanical pressure versus intrinsic effects of hypertension on large arteries in humans. Hypertension. 1991. 18:657-664.