Signaling via the Tgf-beta type I receptor Alk5 in heart development.

University of Michigan, Department of Biologic and Materials Sciences, Ann Arbor, MI 48109, USA.
Developmental Biology (Impact Factor: 3.64). 09/2008; 322(1):208-18. DOI: 10.1016/j.ydbio.2008.07.038
Source: PubMed

ABSTRACT Trophic factors secreted both from the endocardium and epicardium regulate appropriate growth of the myocardium during cardiac development. Epicardially-derived cells play also a key role in development of the coronary vasculature. This process involves transformation of epithelial (epicardial) cells to mesenchymal cells (EMT). Similarly, a subset of endocardial cells undergoes EMT to form the mesenchyme of endocardial cushions, which function as primordia for developing valves and septa. While it has been suggested that transforming growth factor-betas (Tgf-beta) play an important role in induction of EMT in the avian epi- and endocardium, the function of Tgf-betas in corresponding mammalian tissues is still poorly understood. In this study, we have ablated the Tgf-beta type I receptor Alk5 in endo-, myo- and epicardial lineages using the Tie2-Cre, Nkx2.5-Cre, and Gata5-Cre driver lines, respectively. We show that while Alk5-mediated signaling does not play a major role in the myocardium during mouse cardiac development, it is critically important in the endocardium for induction of EMT both in vitro and in vivo. Moreover, loss of epicardial Alk5-mediated signaling leads to disruption of cell-cell interactions between the epicardium and myocardium resulting in a thinned myocardium. Furthermore, epicardial cells lacking Alk5 fail to undergo Tgf-beta-induced EMT in vitro. Late term mutant embryos lacking epicardial Alk5 display defective formation of a smooth muscle cell layer around coronary arteries, and aberrant formation of capillary vessels in the myocardium suggesting that Alk5 is controlling vascular homeostasis during cardiogenesis. To conclude, Tgf-beta signaling via Alk5 is not required in myocardial cells during mammalian cardiac development, but plays an irreplaceable cell-autonomous role regulating cellular communication, differentiation and proliferation in endocardial and epicardial cells.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Lymphatic vasculature is increasingly recognized as an important actor both in the regulation of normal tissue homeostasis and immune response, and in many diseases, such as inflammation, cancer, obesity and hypertension. In the past few years, in addition to the central role of VEGF-C/VEGFR-3 signaling in lymphangiogenesis, significant new insights were obtained about Notch, TGFβ/BMP, Ras, MAPK, PI3 kinase and Ca(2+)/calcineurin signaling pathways in the control of growth and remodeling of lymphatic vessels. An emerging picture of lymphangiogenic signaling is complex, and in many ways distinct from the regulation of angiogenesis. This complexity provides new challenges, but also new opportunities for selective therapeutic targeting of lymphatic vasculature.
    Blood 03/2014; · 9.78 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Despite advances in the treatment of heart failure, mortality remains high, particularly in individuals with diabetes. Activated transforming growth factor beta (TGF-beta) contributes to the pathogenesis of the fibrotic interstitium observed in diabetic cardiomyopathy. We hypothesized that high glucose enhances the activity of the transcriptional co-activator p300, leading to the activation of TGF-beta via acetylation of Smad2; and that by inhibiting p300, TGF-beta activity will be reduced and heart failure prevented in a clinically relevant animal model of diabetic cardiomyopathy.
    Cardiovascular Diabetology 05/2014; 13(1):89. · 3.71 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Angiogenesis, the formation of new blood vessels from pre-existing vessels, in the central nervous system (CNS) is seen both as a normal physiological response as well as a pathological step in disease progression. Formation of the blood-brain barrier (BBB) is an essential step in physiological CNS angiogenesis. The BBB is regulated by a neurovascular unit (NVU) consisting of endothelial and perivascular cells as well as vascular astrocytes. The NVU plays a critical role in preventing entry of neurotoxic substances and regulation of blood flow in the CNS. In recent years, research on numerous acquired and hereditary disorders of the CNS has increasingly emphasized the role of angiogenesis in disease pathophysiology. Here, we discuss molecular mechanisms of CNS angiogenesis during embryogenesis as well as various pathological states including brain tumor formation, ischemic stroke, arteriovenous malformations, and neurodegenerative diseases.
    Cellular and Molecular Life Sciences CMLS 04/2014; · 5.86 Impact Factor

Full-text (2 Sources)

Available from
May 19, 2014