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Expressional Regulation of the Angiopoietin-1 and -2 and the Endothelial-Specific Receptor Tyrosine Kinase Tie2 in Adrenal Atrophy: A Study of Adrenocorticotropin-Induced Repair

Equipe Mixte Institut National de la Santé et de la Recherche Médicale (INSERM) (EMI 02-19), Laboratoire de Développement et Vieillissement de L’Endothélium (O.F., I.V.); and INSERM EMI 01-05 (C.M.), Département Réponse Dynamique Cellulaire, Commissariat à l’Energie Atomique, 38054 Grenoble Cedex 9, France

Address all correspondence and requests for reprints to: Dr. Isabelle Vilgrain, Commissariat à l’Energie Atomique, Grenoble, Département Recherche Dynamique Cellulaire, INSERM EMI 02-19, Laboratoire de Développement et Vieillissement de l’Endothélium, 17 rue des Martyrs, 38054 Grenoble Cedex 9, France. E-mail: ivilgrain{at}cea.fr.

Angiopoietin-1 (Ang-1), a newly discovered ligand of the endothelial-specific tyrosine kinase receptor Tie-2, has been found to promote cell survival, vascular maturation, and stabilization, and to function in concert with vascular endothelial growth factor. Adrenal gland has an intense capillary network that regulation remains to be documented. Recently, we demonstrated that vascular endothelial growth factor, and its receptors are expressed in mouse adrenal in vivo, but no detailed study on Ang expression in the adrenal has been reported. The present study shows the expression of Tie2 receptors, Ang-1, and its endogenous antagonist, Ang-2 in mouse adrenal in vivo. Immunohistochemistry disclosed that Tie2 colocalized with platelet-endothelial-cell-adhesion-molecule in endothelial cells from normal mouse adrenal. Daily administration of dexamethasone (DEX) (0.5 mg/100 g body weight·d) for 6 d in mice, decreased steroidogenic function of adrenal as shown by inhibition of the 36-kDa ACTH receptor protein expression, and decreased plasma corticosterone level [control from 465 ± 35 ng/ml to 114 ± 18 ng/ml in DEX group (P < 0.001)]. Using semiquantitative RT-PCR, we demonstrate that DEX treatment down regulates Ang-1 mRNA levels by 3- to 4-fold. No significant changes in Ang-2 were detected between control and DEX groups, resulting in an altered Ang-2 to Ang-1 relative ratio. The Tie2 receptor was also found to be down-regulated in DEX group at both mRNA and protein level. ACTH was found to play a causal role in DEX-induced decrease in Ang-1/Tie2 system, because 7 d treatment with long acting 1–39 ACTH (30 IU/kg·d) increased Ang-1, Tie2 expression, and plasma corticosterone back to control levels. These results reinforce the role of ACTH in the regulation of angiogenic factors in adrenal gland and suggest that the Ang/Tie2 system might represent a key player for stabilization of adrenal endothelium.

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