Abstract 17462: Relevance of Regulatory T Cells to Gender Dimorphism in Pulmonary Hypertension

• Published in: Circulation (New York, N.Y.) N.Y.), 2015-11, Vol.132 (Suppl_3 Suppl 3), p.A17462-A17462
• Main Authors: Tamosiuniene, Rasa, Nguyen, Linh, Luria, Ayala, Sante, Joshua, Saito, Toshie, Rabinovitch, Marlene, Voelkel, Norbert, Habtezion, Aida, Nicolls, Mark
• Format: Article
• Language: English
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/circ.132.suppl_3.17462

Idiopathic Pulmonary Arterial Hypertension (IPAH) is a disease with female predominance. A growing body of evidence shows reciprocal relationship between sex steroids and the immune system. The aim of the present study was to determine whether the absence of Tregs with the presence of endogenous estrogen mediate the development of PH in a gender-specific manner and if protective signaling pathways of Tregs prevent gender dimorphism of PH susceptibility in T cell deficient animal model of PH.Methods and Resultsin two utilized models of PH inbred Wag T cell deficient athymic (AT) nude male and female rats were given s/c SU5416 in normoxia or treated with chronic hypoxia (CH) for 21d. In IR experiments, AT rats received purified CD4+CD25+hi/Tregs. We also tested the effect of murine/human Tregs or CD4+CD25- on primary rat lung, cardiac and human lung microvascular ECs (RLMECs, HLMECs, RCMECs) with set-up of cocultures.In both PH models treatment resulted in development of PH with significantly higher RVSP and particular significantly pronounced RVH in female than in male in both SU5416 and CH groups (Fulton index0.41±0.01vs.0.33±0.02 and 0.52±0.03vs.0.37±0.01, p< 0.05). However, circulating estrogen levels were found to be significantly elevated in female than in male in all animal groups. For both female and male AT animals IR of Tregs prevented PH with RV remodeling, as well as decreased perivascular fibrosis and increased estrogen receptor (ER)β expression in lung and RV vascular wall.In vitro studies on coculture of Tregs with RLMECs and RCMECs resulted in an upregulation of IL-10, HO-1, PDL1, ERα, ERβ, activation of pAKT pathway, and endothelial nitric oxide synthase (eNOS), which was abrogated with ER antagonist ICI182,780.In addition, compared with control male AT rats, control female animals had increased expression of HO1, HO2 enzymes in lung and RV vascular wall endothelial/Reca+ cells as well as increased capillary density in RV. Thus, differential HO expression between the genders might account for the PH susceptibility.ConclusionsOur data suggest that Tregs signaling is required as a major mechanism with possible mutual interaction of endogenous estrogen to prevent endothelial injury related gender dimorphism for the development of PH.