β-adrenergic signalling and angiogenesis
keywords: propranolol, hemangioma, vasculogenesis, anti-angiogenic therapy, metabolism
Systemic administration of propranolol, a non selective ß adrenergic receptor antagonist, can stop the growth phase of cutaneous infantile haemangiomas (IH), and accelerates tremendously their involution. The field of application of this discovery now comprises non-cutaneous lesions, other vascular lesions, and remodeling of vessels during neovascularisation, a so far neglected role for beta-adrenoreceptors (bAR). These receptors, which are belong to the R7G family of receptors coupled to G-proteins, are expressed in most mammalian tissues. Their activation affect the expression of several genes including VEGF (Vascular Endothelial Growth Factor) and bFGF (basic Fibroblast Growth Factor) via cAMP and Raf pathway. The main objective of our project is to understand the observed effect of propranolol in IH and to translate this knowledge to adrenergic control of normal and dysregulated vasculogenesis. We have recently identified several potential cellular targets of propranolol in infantile hemangioma (IH) including the vascular structures (endothelial cells and pericytes) and microenvironment (mastocytes).
Our first objective is to understand the mechanism underlying the effects of propranolol on IH. To this end, the bAR signaling pathway will be modified in different cell types composing a hemangioma tumor. Particularly, we are investigating the role of oxidative and energy metabolism as the downstream targets of activated bAR. Our second objective is to investigate whether propranolol could be used as an adjuvant treatment in cancer therapy, especially in skin cancers. To this end, different in vitro and in vivo mouse models will be used. This basic science project is closely associated with a clinical research on hemangioma and vascular malformations at the reference center for rare skin disorders (responsible Dr. Léauté-Labrèze).
- Stay in NICU and infantile haemangioma development. Gey A, Ezzedine K, Diallo A, Prey S, Dreyfus I, Maza A, Mazereeuw-Hautier J, Taieb A, Léauté-Labrèze C. J Eur Acad Dermatol Venereol. (2015-03) 29(3):566-73
- A randomized, controlled trial of oral propranolol in infantile hemangioma. Léauté-Labrèze C, et al. N Engl J Med. (2015-02-19) 372(8)
- Mast cells as possible targets of propranolol therapy: an immunohistological study of beta-adrenergic receptors in infantile haemangiomas. Prey S, Leaute-Labreze C, Pain C, Moisan F, Vergnes P, Loot M, Taieb A, Cario-Andre M. Histopathology. (2014-09) 65(3):436-9
- Factors associated with the relapse of infantile haemangiomas in children treated with oral propranolol. Ahogo CK, Ezzedine K, Prey S, Colona V, Diallo A, Boralevi F, Taieb A, Léauté-Labrèze C. Br J Dermatol. (2013-11) 169(6):1252-6
- Propranolol for severe hemangiomas of infancy. Léauté-Labrèze C, Dumas de la Roque E, Hubiche T, Boralevi F, Thambo JB, Taieb A. N Engl J Med. (2008) 358:2649-51
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