Biomedical subjects

Luca Carta

Publications and source records attributed to Luca Carta.

5 recordsLinked to original sources

PubMed2006

Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome.

Aortic aneurysm and dissection are manifestations of Marfan syndrome (MFS), a disorder caused by mutations in the gene that encodes fibrillin-1. Selected manifestations of MFS reflect excessive signaling by the transforming growth factor-beta (TGF-beta) family of cytokines. We show that aortic aneurysm in a mouse model of MFS is associated with increased TGF-beta signaling and can be prevented by TGF-beta antagonists such as TGF-beta-neutralizing antibody or the angiotensin II type 1 receptor (AT1) blocker, losartan. AT1 antagonism also partially reversed noncardiovascular manifestations of MFS, including impaired alveolar septation. These data suggest that losartan, a drug already in clinical use for hypertension, merits investigation as a therapeutic strategy for patients with MFS and has the potential to prevent the major life-threatening manifestation of this disorder.

Adrenergic beta-Antagonists↗

PubMed2005

Fibrillins 1 and 2 perform partially overlapping functions during aortic development.

Fibrillin-rich microfibrils are extracellular assemblies that impart structural properties to the connective tissue. To elucidate the contribution of fibrillin-rich microfibrils to organogenesis, we have examined the vascular phenotype of a newly created strain of mice that completely lacks fibrillin-1 and the consequences of combined deficiency of fibrillins 1 and 2 on tissue formation. The results demonstrated that fibrillins 1 and 2 perform partially overlapping functions during aortic development. Fbn1-/- mice died soon after birth from ruptured aortic aneurysm, impaired pulmonary function, and/or diaphragmatic collapse. Analysis of the neonatal Fbn1-/- aorta documented a disorganized and poorly developed medial layer but normal levels of elastin cross-links. Transcriptional profiling revealed that aneurysm progression in Fbn1 null mice is accompanied by unproductive up-regulation of gene products normally involved in tissue repair and vascular integrity, such as plasminogen activator inhibitor-1, activin A, and cysteine-rich angiogenic protein 61. In contrast to Fbn1-/- mice, Fbn2 null mice had a well developed and morphologically normal aortic wall. However, virtually all Fbn1-/-;Fbn2-/- embryos and about half of the Fbn1+/-;Fbn2-/- embryos died in utero and displayed a significantly more severe vascular phenotype than Fbn1-/- mice. Consistent with a specialized function of fibrillin-2, electron microscopy visualized ultrastructurally different microfibrils in Fbn1 null compared with control cell cultures. Collectively, these data demonstrate that involvement of fibrillin-2 in the initial assembly of the aortic matrix overlaps in part with fibrillin-1 and that continued fibrillin-1 deposition is absolutely required for the maturation and function of the vessel during neonatal life.

Activins↗

PubMed2005

Recent progress towards a molecular understanding of Marfan syndrome.

Marfan syndrome (MFS) is a systemic disorder of the connective tissue that is inherited as an autosomal dominant trait and which displays variable manifestations in the ocular, skeletal, and cardiovascular systems. These pleiotropic manifestations are accounted for by mutations in fibrillin-1, the building block of extracellular microfibrils. During the past 10 years, we have witnessed significant progress in delineating the pathological events responsible for the manifestations of MFS. Much of this progress has been based on the creation and analysis of fibrillin-1 mutant mouse lines that faithfully recapitulate the spectrum of clinical severity of MFS. These studies have established the critical contribution of fibrillin-1 deficiency to disease progression through altered cell-matrix interactions and dysregulated TGF-beta signaling. As a result, our definition of MFS as the prototypical structural disorder of the connective tissue has changed to that of a developmental abnormality with broad and complex effects on the morphogenesis and function of multiple organ systems. Importantly, new biological targets have emerged that may yield exciting new opportunities for the development of productive treatment strategies in MFS.

Animals↗

PubMed2005

Diethylstilbestrol exposure in utero: a paradigm for mechanisms leading to adult disease.

The synthetic estrogen diethylstilbestrol (DES) was administered to pregnant women between the 1940s and the mid-1970s and is believed to be responsible for numerous uterine/cervical/vaginal malformations and cancers that appeared after birth and in young adult life. This medical tragedy has served as one of the prototypical examples of a phenomenon known as "endocrine disruption," in which either environmental agents or other compounds disrupt normal hormonal signaling in the body. Whereas DES signals through estrogen receptors, the subsequent molecular targets were largely unknown. We had identified Wnt7a as a target in this pathway and have used genetic analyses of mutant mice to demonstrate that disruption of Wnt7a is the key event leading to the DES phenotypes and cancers. We find that Wnt7a expression is only transiently deregulated in response to DES exposure, leading to the conclusion that critical events during early reproductive tract development results in a permanent change or "reprogramming" in subsequent development.

Animals↗

PubMed2004

Wnt7a is a suppressor of cell death in the female reproductive tract and is required for postnatal and estrogen-mediated growth.

The murine female reproductive tract is undifferentiated at birth and undergoes pronounced growth and cytodifferentiation during postnatal life. Postnatal reproductive tract development proceeds in the absence of high levels of circulating estrogens and is disrupted by precocious exposure to estrogens. The WNT gene family is critical in guiding the epithelial-mesenchymal interactions that direct postnatal uterine development. We have previously described a role for Wnt7a in controlling morphogenesis in the uterus. In addition to patterning defects, Wnt7a mutant uteri are atrophic in adults and do not show robust postnatal growth. In the present study, we examine immature female Wnt7a mutant and wild-type uteri to assess the cellular processes that underlie this failure in postnatal uterine growth. Levels of proliferation are higher in wild-type versus Wnt7a mutant uteri. Exposure to the potent estrogen-agonist diethylstilbestrol (DES) leads to an increase in cell proliferation in the uterus in wild-type as well as in mutant uteri, indicating that Wnt7a is not required in mediating cell proliferation. In contrast, we observe that Wnt7a mutant uteri display high levels of cell death in response to DES, whereas wild-type uteri display almost no cell death, revealing that Wnt7a plays a key role as a cell death suppressor. The expression pattern of other key regulatory genes that guide uterine development, including estrogen receptor (alpha), Hox, and other WNT genes, reveals either abnormal spatial distribution of transcripts or abnormal regulation in response to DES exposure. Taken together, the results of the present study demonstrate that Wnt7a coordinates a variety of cell and developmental pathways that guide postnatal uterine growth and hormonal responses and that disruption of these pathways leads to aberrant cell death.

Animals↗