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Linking a serotonin transporter polymorphism to vascular smoothmuscle proliferation in patients with primary pulmonary hypertension
Marlene Rabinovitch
Departments of Pediatrics, Laboratory Medicine and Pathobiology, and Medicine, University of Toronto, Cardiovascular Research Program, Research Institute, The Hospital for Sick Children, 555 University Avenue, 7003 McM, Toronto, Ontario, Canada M5G1X8.
Phone: (416) 813-5918; Fax: (416) 813-7480; E-mail: mr@sickkids.on.ca.
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Published October 15, 2001 - More info
J Clin Invest. 2001;108(8):1109–1111. https://doi.org/10.1172/JCI14205.
© 2001 The American Society for Clinical Investigation
Recent genetic studies in patients with familial and sporadic primary pulmonary hypertension (PPH) have provided new opportunities to address the pathophysiologic mechanisms of this disease (1, 2). This past year, mutations in the bone morphogenetic protein receptor 2 (BMPR2) gene have been identified in even a higher proportion of individuals than was first appreciated (3). In addition, mutations associated with impaired signaling through other members of the TGF-β receptor family have also been uncovered (4). How aberrant processing of these signals is related to the cellular mechanisms previously described in patients with pulmonary hypertension remains to be completely elucidated. In addition, we need to understand how other kinds of stimuli, such as inflammatory disorders associated with collagen vascular disease, mechanical forces related to congenital heart defects, and serotonin analogs like the appetite suppressant dexfenfluoramine, initiate cellular abnormalities that lead to severe progressive pulmonary hypertension.
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Cross-talk with TGF-β signaling pathways
It is not readily apparent why patients without the polymorphism show a higher than normal proliferative response to 5-HT. Perhaps undiscovered polymorphisms in other components of the 5-HT pathway, such as receptors or downstream effectors, also promote PPH. In this regard, it would be of great interest to determine how the 5-HTT pathway is affected by a common BMPR2 mutation, which has been implicated in over 50% of individuals with familial and about 25% of those with sporadic PPH. The authors allude to work in which normal signaling from BMPR2 is associated with suppression of smooth muscle cell proliferation (10, 11) and hence may antagonize the effects of 5-HT (Figure 1). The BMPR2 mutation could therefore allow for a heightened response to 5-HT, particularly in patients with a polymorphism allowing for heightened expression of the 5-HTT. To characterize the interaction between BMP and 5-HT signaling, it will be important to identify patients carrying both the 5HTT polymorphism and the BMPR2 mutation and to study the proliferative responses of their smooth muscle cells. This analysis could indicate how aberrant BMPR2 signal transduction and gene expression is complementary to increased 5-HTT signaling and gene expression in inducing cell proliferation. For example, do the signals induced by 5-HT and those suppressed by BMPR2 ligands influence the transactivating ability of the same set of transcription factors and the expression of the same target genes?
Figure 1Hypothetical interaction between the pathways regulated by the bone morphogenetic protein receptor ligands and the serotonin (5-HT) transporter. Here, BMP receptor ligands are proposed to suppress transactivation of genes associated with smooth muscle proliferation by maintaining transcription factors (TF) bound to Smad proteins. Activation of the 5-HT transporter is normally antagonized by this pathway unless BMP receptor ligands are mutated or there is a polymorphism of 5-HT allowing for overexpression.
In addressing the cellular biology of PPH, the proliferative response of the pulmonary artery smooth muscle cell is only one facet of the disease. Indeed, despite high 5-HT levels and transport, hypoxia-induced pulmonary hypertension (PH) is a reversible condition largely characterized by thickened vessels in which there are relatively modest cell proliferation and no increase in cell migration, as occurs in the characteristic obliterative lesions found in clinical PPH. Hence there may be other factors contributing to the disease process.
It has not been addressed how the proliferative response is related to other features of neointimal formation in advanced pulmonary vascular lesions, such as smooth muscle cell migration, the increased elaboration of ECM (12), or endothelial proliferation (13). For example, increased expression of growth factors, such as TGF-β, have been observed in patients (14) and in experimental models (15) of PH, and cells from patients with pulmonary hypertension are more highly responsive to the proliferative effect of TGF-β (10). In addition, our group has shown in experimental animals that heightened serine elastase activity (16) liberates mitogenic growth factors from the ECM and promotes vascular smooth muscle cell proliferation (17). Serine elastase can also initiate a proteolytic cascade that appears necessary for the induction of tenascin, a glycoprotein whose expression is also coupled to smooth muscle proliferation (12, 18, 19). In cultured vascular smooth muscle cells, tenascin amplifies the proliferative response to growth factors by facilitating the phosphorylation of growth factor receptors (19).
It would also be of interest to explore the relationship between the 5HTT polymorphism and heightened pulmonary hypertension in the fawn hooded rat (20, 21), which shows increased serotonin release and increased pulmonary hypertension in response to hypoxia but is free from other, more severe structural abnormalities. The role of serotonin in the pulmonary hypertensive phenotype has recently been called into question (21).
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