© 2003 by European Society of Cardiology
Copyright © 2003, European Society of Cardiology
The tantalizing triplet of pulmonary hypertension—BMP receptors, serotonin receptors, and angiopoietins
Department of Medicine, University of Giessen School of Medicine, Aulweg 123, 35392 Giessen, Germany
*Corresponding author. Tel.: +49-641-9942300; fax: +49-641-9942309. Email address: oliver.eickelberg{at}innere.med.uni-giessen.de
See article by Blanpain et al. (pages 518–528) in this issue.
Not many diseases have attracted as much attention by the basic and clinical research community during the last several years as has idiopathic pulmonary arterial hypertension (IPAH, formerly primary pulmonary hypertension). IPAH is a severe and progressive disease localized exclusively to the lung, which exhibits an abnormally elevated precapillary pulmonary vascular resistance due to vasoconstriction and remodelling of the pulmonary vascular system. The underlying histological abnormalities consistently found in severe disease are obstructive and concentric lesions of small pulmonary resistance arterioles, which lead to an elevated pulmonary arterial pressure of >25 mm Hg at rest or >30 mm Hg during exercise. These lesions are thought to be due to enhanced proliferation of endothelial and/or smooth muscle cells or to the local transformation of quiescent fibroblasts into smooth muscle cells. The elevated pulmonary vascular pressure leads to progressive right heart hypertrophy and eventual failure, often resulting in death if undiagnosed and untreated [1,2].
Although IPAH mostly occurs as a sporadic disease, a subset of patients was identified as early as 1954 who exhibited a family history of the disease [3]. This led to the identification of several cases of familial IPAH [4], which now represents an autosomal dominant disorder with incomplete penetrance. For a long time, familial IPAH was considered a mysteriously devastating disease of unknown etiology. However, recent genetic linkage studies have revealed at least one definite PPH1 locus on chromosome 2q31–32 [5,6]. In 2000, positional cloning revealed that the causative factor for familial IPAH within the PPH1 locus was BMPR2, the gene encoding bone morphogenetic protein receptor (BMPR) II [7,8]. Direct sequence analysis has identified multiple heterogeneous germline mutations in BMPR2 exons in more than 50% of the families that are predicted to lead to a variety of missense, nonsense, or frameshift mutations. This discovery has led to the emergence of several functional genomic studies investigating the role of this receptor in disease pathogenesis and how the uncovered mutations would alter signal transduction of BMPRII [9,10]. Despite these efforts, however, it remains entirely enigmatic how these heterozygous mutations in one allele can cause or trigger such a complex yet compartmentalized disease.
In this issue of Cardiovascular Research, a study by Cedric Blanpain et al. from the Free University of Brussels highlights another system that seems to play a major role in the pathophysiology of IPAH. This group identified a heterozygous loss-of-function mutation in the 5-HT2B receptor in one patient with fenfluramine-associated PH (insert reference once formatted). Fenfluramine, a serotonin agonist, was widely used as an appetite suppressant during the nineties before it was found that exposure to fenfluramine (or dexfenfluramine) represented a definite risk factor for the development of PH [11]. Blanpain et al. now describe a C to T mutation in one of ten patients investigated, which led to substitution of a stop codon instead of an arginine in the C-terminus of the 5-HT2B receptor. The described mutation leads to the truncation of the protein at AA 393 (R393X), resulting in the loss of putative palmitoylation and phosphorylation sites. The mutation was not found in 80 control patients and 18 patients with PH not associated with fenfluramine intake. In spite of the low incidence of this mutation, Blanpain et al. also present functional data indicating that the mutation may be linked to disease pathogenesis. The mutant R393X was expressed normally and exhibited normal ligand binding in COS cells but was unable to initiate signal transduction as measured by calcium release. R393X, however, did not act as a dominant-negative receptor in this system, and it remains to be shown whether this or another mutation in the 5-HT2B receptor is present in more than one patient with PH.
In this way, the story very much resembles the findings of heterozygous loss-of-function mutations of BMPRII in PH, many of which do not act as dominant-negatives on the wild-type receptor. Interestingly, a study by Humbert et al. has investigated the BMPR2 locus in patients with fenfluramine-associated PH, and this group has described that 
9% of such patients exhibited BMPR2 mutations [12]. Abramowicz et al. [13] have also recently presented a case study of a 27-year-old female with appetite-suppressant-associated PH and a BMPR2 mutation (albeit this patient used amfepramone and not fenfluramine). It thus seems that BMPRII and 5-HT2B receptor mutations occur independently of each other in affected individuals. It would thus be of great interest in the future to determine how the action of one affects the other functionally, as inactivation of one system by reduced activity of the other may trigger onset of the disease.
With these recent findings at hand, we are now left puzzled about the complexity and heterogeneity of the disease. Taking all genetic and functional studies into account, however, a nucleus of core mediators (or rather suspects) slowly begins to crystallize. Three important systems may present a core around which future studies will synergize to unravel the pathobiology of PH: the BMP/TGF-β system, the serotonin system, and the angiopoietin system.
Interest in the BMP system in PH began when the above described germline mutations in BMPR2 were initially discovered and then confirmed. BMP signal transduction is initiated after binding of BMP ligands to their cognate BMPRI and BMPRII receptors. The constitutive active BMPRII kinase then transphosphorylates the type I receptor kinase, which activates intracellular signaling processes by phosphorylation and thus activation of Smads and p38 MAP kinase [14]. Although BMPRII is not the high affinity ligand receptor for most BMP isoforms, it is generally accepted that its interaction with a type I BMP receptor (ALK3/BMPRIa or ALK-6/BMPRIb) is required for proper signal propagation by BMP ligands. Significant attention has focused on determining the pathophysiological mechanisms by which such heterozygous germline mutations in BMPR2 contribute to the development of severe PH. Heterozygous mutations in BMPR2 have been found in approximately 55% of familial IPAH patients and roughly 30% of patients with sporadic IPAH. Interestingly however, germline BMPR2 mutations are neither necessary nor sufficient to cause PH, and we are thus challenged with finding a trigger or "second-hit" that is required for disease onset.
One possible trigger is the serotonin system. Initially proposed as a possible mediator of PH in a patient with a rare familial platelet storage deficiency [15], serotonin has evolved into a prime candidate as a causative agent of PH. Serotonin is a potent pulmonary vasoconstrictor and mitogen for pulmonary smooth muscle cells, and overexpression of the serotonin transporter 5-HTT leads to PH in an animal model [16]. Furthermore, PH in humans and animal models is associated with overexpression of the 5-HT2B receptor, and blocking or absence of the receptor leads to inhibition of disease progression in mice [17]. In this respect, it remains to be seen how the described loss-of-function mutation in the 5-HT2B receptor fits into the current picture of serotonin and PH, as it is predicted to lead to an inhibition of serotonin effects.
Dysregulation of the serotonin and BMP systems also occurs in models with perturbations of the third suspected cause of PH, the angiopoietin system. Still somewhat controversial and largely described by one group, consistent overexpression of angiopoietin-1 (ang-1) was found in lungs of all PH patients investigated, irrespective of the underlying cause [18]. In this study, ang-1 overexpression was linked to a dramatic loss of BMPRIa expression in the lungs of all patients investigated, and thus proposed to cause the disease by interfering with the BMP system. A recent study by the same group has generated an animal model of PH by viral overexpression of ang-1 in the pulmonary vasculature [19]. This animal model develops PH with characteristic lesions and features, and cultured endothelial cells from the animals exhibit enhanced serotonin production. However, the potential effects of ang-1 overexpression on BMPRIa levels in this model were not reported.
Thus, it seems that the circle is closing and all three suspects are part of a tantalizing triplet that probably will give further clues about the etiology of the disease in the future. We are still at the beginning of characterizing the physiological effects of BMPs, angiopoietins, and serotonin in the pulmonary vasculature, and much effort will be required to elucidate these effects. Only then can we try to understand how perturbations of these systems contribute to the development of such a complex disease, and we may then begin to think about manipulation of these systems for future therapeutic regimen.
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