The pharmacology of the pulmonary circulation: changes in pulmonary hypertension

Pulmonary hypertension occurs when the blood vessels of the lungs narrow and close off and the pressure within the blood vessels gets very high. This means that blood is no longer filled with oxygen. This puts strain on the right side of the heart and this fails.  We study chemicals that cause pulmonary hypertension such as serotonin. Recently we have been looking at the effects of oestrogens on the pulmonary arteries to discover why women get the disease more than men.

The main focus over the last 30 years has been to understand the pharmacology of the pulmonary circulation and how this is altered by pulmonary hypertension. The research integrates clinical, in vivo pharmacology with in vitro and cellular studies. The research group is unique in the number of models of pulmonary hypertension it holds, has characterised or developed: pulmonary hypertension secondary to left ventricular function in a coronary ligated rabbit model; the chronic hypoxic rat and mouse; the mouse over-expressing the serotonin transporter; the fawn-hooded rat, the SUGEN/hypoxic rodent and the monocrotaline rat.
MacLean’s research group has contributed to understanding the roles of endothelin-1, phosphodiesterase 5 (PDE5), the serotonin transporter, the 5-HT1B receptor and tryptophan hydroxlase 1 (Tph1) in the development of pulmonary hypertension. Bosentan (®Tracleer, endothelin antagonist) and Sildenafil (®Revatio, PDE5 inhibitor) are licensed for the treatment of pulmonary hypertension. Serotonin uptake inhibitors are into Phase 2 clinical trials, novel 5HT1B receptor antagonist are under development and pharmaceutical companies are developing Tph1 inhibitors as a potential therapeutic strategy. Hence this work is strongly translational and continues to contribute to novel therapeutic strategies.
Recent key findings: 1. First direct evidence for the serotonin hypothesis of dexfenfluramine-induced pulmonary hypertension. (Circulation 2008). 2. First direct evidence that peripheral serotonin is required for the development of hypoxia-induced pulmonary hypertension. (Hypertension, 2007). 3. Evidence that serotonin increases susceptibility to pulmonary hypertension in BMPR2-deficient mice (Circ Res, 2006). 4. 5HT1B receptors and SERT interact to mediate pulmonary vasoconstriction and proliferation (Circ Res, JPET, 2005). 5. Over-expression of SERT predisposes to PAH and hypoxia-induced PAH (Circulation, 2004). 6. The 5HT1B receptor plays a pivotal role in the development of experimental PAH (14 publications to date). 7. Characterisation of novel models of PAH where there is gender specificity. 8. Role of CYP1B1 and oestrogen metabolism in the development of PAH (Circulation, 2012). Hence work has been pivotal in determining the role of serotonin, gender and oestrogens in PAH and these findings are consistently published in high impact journals.

Publications

1. MacLean MR, Deuchar GA, Hicks MN, Morecroft I, Shen S, Sheward J, Colston J, Loughlin L, Nilsen M, Dempsie Y & Harmar A. Over-expression of the 5-hydroxytryptamine transporter gene: effect on pulmonary haemodynamics and hypoxia-induced pulmonary hypertension. Circulation 2004;109:2149-2154
2. Lawrie A, Spiekerkoetter E, Martinez E, Ambartsumian N, Sheward J, MacLean MR, Harmar A, Schmidt A-M, Lukanidin E and Rabinovitch M. Interdependent serotonin transporter and receptor pathways regulate S100A4/Mts 1, a gene associated with cancer and vascular disease. Circ. Res. 2005;97:227-235.
3. Long L, MacLean MR, Jeffery TK, Morecroft I, Rudarakanchana N, Southwood M, James V, Trembath RC & Morrell NW. Serotonin increases susceptibility to pulmonary hypertension in BMPR2-deficient mice Circ. Res. 2006;98:818-827.
4. Dempsie Y, Morecroft I, Welsh J, MacRitchie NJ, Herold N, Loughlin L, Nilsen M, Peacock AJ, Harmar A, Bader M &. MacLean MR. Converging evidence in support of the serotonin hypothesis of dexfenfluramine-induced pulmonary hypertension using novel transgenic mice. Circulation 2008;117:2928-2937
5. Morecroft I, Dempsie Y, Bader M, Walther DJ, Kotnik K, Loughlin L, Nilsen M & MacLean MR. Effect of tryptophan hydroxylase 1 deficiency on the development of hypoxia-induced pulmonary hypertension. Hypertension 2007;49:232-6.
6. White, K, Dempsie, Y, Nilsen, M, Wright, AF, Loughlin, L & MacLean, MR. Serotonin Transporter, Gender and 17β Oestradiol in the Development of Pulmonary Arterial Hypertension. Cardiovasc Res. 2011;90:373-82
7. White K, Loughlin L, Maqbool Z, Nilsen M, McClure J, Dempsie Y, Baker AH & MacLean MR. The serotonin transporter, gender and hypoxia: Microarray analysis in the pulmonary arteries of mice identifies genes with relevance to human PAH. Physiol Genomics 2011; 43:417-37.
8. White K, Johansen KA, Nilsen M, Ciuclan L, Wallace E, Paton L, Campbell A, Morecroft I, Loughlin L, McClure J, Thomas M, Mair KM and MacLean MR Activity of the estrogen metabolising enzyme cytochrome P450 1B1 influences the development of pulmonary arterial hypertension. Circulation 2012;126:1087-98.
9. Ciuclan L, Hussey MJ, Burton V, Good R, Duggan N, Beach S, Jones P, Fox R, Clay I, Bonneau O, Konstantinova I, Pearce A, Rowlands DJ, Jarai G, Westwick J, MacLean MR, Thomas M. Imatinib attenuates hypoxia-induced PAH pathology via reduction in 5-HT through inhibition of TPH1 expression. American Journal of Respiratory and Critical Care Medicine 2013;187:78-89