Search

Background: Latent TGFβ binding protein‐2 (LTBP2) is a fibrillin 1 binding component of the microfibril. LTBP2 is the only LTBP protein that does not bind any isoforms of TGFβ, although it may interfere with the function of other LTBPs or interact with other signaling pathways. Results: Here, we investigate mice lacking Ltbp2 (Ltbp2−/−) and identify multiple phenotypes that impact bodyweight and fat mass, and affect bone and skin development. The alterations in skin and bone development are particularly noteworthy since the strength of these tissues is differentially affected by loss of Ltbp2. Interestingly, some tissues that express high levels of Ltbp2, such as the aorta and lung, do not have a developmental or homeostatic phenotype. Conclusions: Analysis of these mice show that LTBP2 has complex effects on development through direct effects on the extracellular matrix (ECM) or on signaling pathways that are known to regulate the ECM. Key Findings: Ltbp2 deficiency results in trabecular bone overgrowthLtbp2 deficiency results in skin alterationsLtbp2 deficiency may impact metabolismLtbp2 deficiency does not result in obvious alterations of lung and aortal tissue [ABSTRACT FROM AUTHOR]

Elastin is an essential component of vertebrate arteries that provides elasticity and stores energy during the cardiac cycle. Elastin production in the arterial wall begins midgestation but increases rapidly during the last third of human and mouse development, just as blood pressure and cardiac output increase sharply. The aim of this study is to characterize the structure, hemodynamics, and mechanics of developing arteries with reduced elastin levels and determine the critical time period where elastin is required in the vertebrate cardiovascular system. Mice that lack elastin ([Eln.sup.-/-]) or have approximately one-half the normal level ([Eln.sup.+/-]) show relatively normal cardiovascular development up to embryonic day (E) 18 as assessed by arterial morphology, left ventricular blood pressure, and cardiac function. Previous work showed that just a few days later, at birth, [Eln.sup.-/-] mice die with high blood pressure and tortuous, stenotic arteries. During this period from El8 to birth, [Eln.sup.+/-] mice add extra layers of smooth muscle cells to the vessel wall and have a mean blood pressure 25% higher than wild-type animals. These findings demonstrate that elastin is only necessary for normal cardiovascular structure and function in mice starting in the last few days of fetal development. The large increases in blood pressure during this period may push hemodynamic forces over a critical threshold where elastin becomes required for cardiovascular function. Understanding the interplay between elastin amounts and hemodynamic forces in developing vessels will help design treatments for human elastinopathies and optimize protocols for tissue engineering. aorta; blood pressure; ultrasound; elastin; mechanics doi: 10.1152/ajpheart.00194.2010.

Mice heterozygous for the elastin gene ([ELN.sup.+/-] ) show unique cardiovascular properties, including increased blood pressure and smaller, thinner arteries with an increased number of lamellar units. Some of these properties are also observed in humans with supravalvular aortic stenosis, a disease caused by functional heterozygosity of the elastin gene. The arterial geometry in [ELN.sup.+/-] mice is contrary to the increased thickness that would be expected in an animal demonstrating hypertensive remodeling. To determine whether this is due to a decreased capability for cardiovascular remodeling or to a novel adaptation of the [ELN.sup.+/-] cardiovascular system, we increased blood pressure in adult [ELN.sup.+/+] and [ELN.sup.+/-] mice using the two-kidney, one-clip Goldblatt model of hypertension. Successfully clipped mice have a systolic pressure increase of at least 15 mmHg over sham-operated animals. [ELN.sup.+/+] and [ELN.sup.+/-]-clipped mice show significant increases over sham-operated mice in cardiac weight, arterial thickness, and arterial cross-sectional area with no changes in lamellar number. There are no significant differences in most mechanical properties with clipping in either genotype. These results indicate that [ELN.sup.+/+] and [ELN.sup.+/-] hearts and arteries remodel similarly in response to adult induced hypertension. Therefore, the cardiovascular properties of [ELN.sup.+/-] mice are likely due to developmental remodeling in response to altered hemodynamics and reduced elastin levels. arterial mechanics; extracellular matrix; high blood pressure; cardiac hypertrophy; two-kidney, one-clip hypertension doi:10.1152/ajpheart.00205.2007

Cigarette smoking is the strongest risk factor for emphysema. However, sensitivity to cigarette smoke-induced emphysema is highly variable, and numerous genetic and environmental factors are thought to mitigate lung response to injury. We report that the quantity of functional elastin in the lung is an important modifier of both lung development and response to injury. In mice with low levels of elastin, lung development is adversely affected, and mice manifest with congenital emphysema. Animals with intermediate elastin levels exhibit normal alveolar structure but develop worse emphysema than normal mice following cigarette smoke exposure. Mechanical testing demonstrates that lungs with low levels of elastin experience greater tissue strains for any given tissue stress compared with wild-type lungs, implying that force-mediated propagation of lung injury through alveolar wall failure may worsen the emphysema after an initial enzymatic insult. Our findings suggest that quantitative deficiencies in elastin predispose to smoke-induce emphysema in animal models and suggest that humans with altered levels of functional elastin could have relatively normal lung function while being more susceptible to smoke-induced lung injury. smoking

Supravalvular aortic stenosis (SVAS) is associated with decreased elastin and altered arterial mechanics. Mice with a single deletion in the elastin gene (EL[N.sup.+/-]) are models for SVAS. Previous studies have shown that elastin haploinsufficiency in these mice causes hypertension, decreased arterial compliance, and changes in arterial wall structure. Despite these differences, EL[N.sup.+/-] mice have a normal life span, suggesting that the arteries remodel and adapt to the decreased amount of elastin. To test this hypothesis, we performed in vitro mechanical tests on abdominal aorta, ascending aorta, and left common carotid artery from EL[N.sup.+/-] and wild-type (C57BL/6J) mice. We compared the circumferential and longitudinal stress-stretch relationships and residual strains. The circumferential stress-stretch relationship is similar between genotypes and changes stress; residual strain; opening angle; compliance; longitudinal

Hypertension and diabetes are common side effects of glucocorticoid treatment. To determine whether peroxisome proliferator-activated receptor-[alpha] (PPAR-[alpha]) mediates these sequelae, mice deficient in low-density lipoprotein receptor (Ldlr[sup.-/-]), with (Ppara[sup.+/+]) or without (Ppara[sup.-/-]) PPAR-[alpha], were treated chronically with dexamethasone. Ppara[sup.+/+], but not Ppara[sup.-/-], mice developed hyperglycemia, hyperinsulinemia and hypertension. Similar effects on glucose metabolism were seen in a different model using C57BL/6 mice. Hepatic gluconeogenic gene expression was increased and insulin-mediated suppression of endogenous glucose production was less effective in dexamethasone-treated Ppara[sup.+/+] mice. Adenoviral reconstitution of PPAR-[alpha] in the livers of nondiabetic, normotensive, dexamethasone-treated Ppara[sup.-/-] mice induced hyperglycemia, hyperinsulinemia and increased gluconeogenic gene expression. It also increased blood pressure, renin activity, sympathetic nervous activity and renal sodium retention. Human hepatocytes treated with dexamethasone and the PPAR-[alpha] agonist Wy14,643 induced PPARA and gluconeogenic gene expression. These results identify hepatic activation of PPAR-[alpha] as a mechanism underlying glucocorticoid-induced insulin resistance., Author(s): Carlos Bernal-Mizrachi [1, 2]; Sherry Weng [1, 2]; Chu Feng [1, 2]; Brian N Finck [1, 5]; Russell H Knutsen [3]; Teresa C Leone [1, 5]; Trey Coleman [1, [...]