INSERM U651 and Département de Physiologie, H™pital H. Mondor, Assistance Publique des H™pitaux de Paris, Créteil, France.
Address correspondence to: Serge Adnot, INSERM U651, Département de Physiologie, Faculté de Médecine de Créteil, 94010 Créteil, France. Phone: 33-1-49-81-36-93, Fax: 33-1-48-98-17-77; E-mail: firstname.lastname@example.org.
First published June 1, 2005 - More info
Hyperplasia of pulmonary artery SMCs (PASMCs) is a pathological hallmark of pulmonary arterial hypertension (PAH). In this issue of the JCI, McMurtry et al. report that adenovirus-mediated overexpression of survivin — a multipotent inhibitor of apoptosis — induces PAH in rats, whereas inhalation of an adenovirus vector encoding a mutant survivin gene with dominant-negative properties reverses established monocrotaline-induced PAH. These findings raise important issues regarding the role of survivin in the pathogenesis of PAH, its value as a prognostic indicator, and its use as a target for new therapeutic strategies.
Pulmonary arterial hypertension (PAH), whether idiopathic (iPAH) or associated with underlying diseases (aPAH), is an unexplained condition for which severe forms in adults or neonates are fatal and no satisfactory treatment is available. Valuable new insights into the disease have stemmed in recent years from genetic studies identifying mutations in the gene encoding bone morphogenic protein receptor type 2 (BMPRII) in patients with familial iPAH (1, 2) and from functional studies showing dysregulation of molecular events governing pulmonary artery SMC (PASMC) proliferation (3). The nature of the primary defect responsible for triggering, maintaining, and arresting PASMC proliferation in PAH is poorly understood but may be either an inherent characteristic of PASMCs (as seen with cancer cells) or a secondary response to an external abnormality, such as upregulation of a growth factor. Under the first hypothesis, cells removed from their in vivo environment would continue to proliferate excessively, whereas under the second hypothesis, their proliferation rate would be normal. An intermediate situation has been found: when removed from their in vivo environment, PASMCs from PAH patients demonstrate excessive proliferation when stimulated by serotonin (5-hydroxytryptamine [5-HT]) or endothelin-1 (ET-1) but not when stimulated by PDGF, EGF, FGF, IGF, or TGF-β (4, 5). Moreover, they are far less sensitive to growth inhibition by bone morphogenic proteins (BMPs) than are normal cells (6). Therefore, the intrinsic abnormalities of these PASMCs involve not intracellular mitogenic signals but rather signal transmission from specific autocrine or paracrine factors such as BMPs, 5-HT, or ET-1. Increased expression of the serotonin transporter (5-HTT), which mediates the proliferative effect of 5-HT, and marked reduction of BMPRII expression appear specific to iPAH and aPAH (4, 7). These molecular alterations occur without apparent genetic abnormalities: in cells without the mutation in BMPRII, the extent of BMPRII underexpression is similar to that in mutated cells (6), and the 5-HTT overexpression can be explained only partly by the polymorphism of its gene promoter (5). Why PASMCs from PAH patients maintain an abnormal phenotype in vitro and how environmental and genetic factors regulate the expression of these key molecular transmitters remain open questions.
Until now, alterations in apoptotic processes have not been considered to play a role in PASMC proliferation, in contrast to mechanisms of disorganized EC proliferation contributing to plexiform lesions at branch points of pulmonary arteries in iPAH (8). In this issue of the JCI, McMurtry et al. open up the intriguing possibility that increased survivin expression may contribute to the abnormal PASMC phenotype observed in PAH (9).
Survivin belongs to the inhibitor of apoptosis protein (IAP) family, members of which confer protection from death-inducing stimuli (10). One of the most striking features of survivin is its differential expression in cancerous versus normal tissues. Survivin is virtually undetectable in normal adult differentiated tissues but is expressed in most human cancers (11). Thus, dysregulated survivin expression is considered to be a major pathologic mechanism of apoptosis inhibition. However, survivin pathway reactivation may occur in normal cell types, most notably vascular cells, including SMCs and ECs. That SMC survival influences abnormal vessel wall remodeling is supported by data from studies of systemic arteries. Vascular injury increases survivin expression in the vessel wall, concomitantly with neointima formation (12). Similarly, McMurtry and colleagues demonstrate that survivin overexpression coincided with pulmonary vascular remodeling in rats developing monocrotaline-induced PAH (9). Thus, survivin overexpression does not precede, but instead occurs downstream of, the remodeling process. Interestingly, in vitro stimulation of SMCs from systemic arteries also induces survivin expression, in keeping with the fact that survivin is regulated in a cell cycle–dependent manner (10). However, in SMCs from systemic arteries, this occurs in response to PDGF but not to EGF, basic FGF, or TGF-β (12). On the other hand, ECs express survivin in response to angiogenic factors that stimulate growth, such as VEGF, but also in response to angiopoietin-1, which on the contrary induces EC quiescence while increasing EC survival (13, 14). Thus, vascular cell stimuli may induce survivin expression, mitogenic signals, or a combination of both (Figure 1). The response may depend on the type of stimulus but may also vary according to the origin and phenotype of the vascular cells. Whether dysregulated survivin expression is associated with the abnormal PASMC phenotype in PAH and whether it is affected selectively by specific growth factors are important questions for future research.
Hypothetical mechanisms leading to hyperplasia of SMCs or ECs in PAH. A number of growth stimuli may act predominantly by inducing mitogenic signals, which may then lead to survivin expression through cell cycle_dependent pathways (cells stimulated by VEGF, PDGF, etc.). Stimuli with a predominant antiapoptotic effect may act on survivin expression chiefly through cell cycle_independent pathways (cells stimulated by IL-1, angiopoietin-1 [Ang1], hypoxia, etc.). The potential effects of factors involved in the pathogenesis of PAH, such as 5-HT, ET-1, TGF-β, and BMPs are unknown.
A major finding from the study by McMurtry et al. (9) is that lung gene transfer of survivin triggers pulmonary vascular remodeling. Antiapoptotic signals and growth factors are believed to act together to produce PASMC proliferation in PAH. The fact that a selective increase in an antiapoptotic signal induces PAH indicates that regulation of the balance between mitotic and apoptotic activity in the normal pulmonary circulation is critical to maintaining pulmonary vessel integrity. Since survivin gene transfer to cultured SMCs does not cause cell growth, this suggests that, in vivo, growth stimuli are continuously delivered to the normal pulmonary vessels. Thus, among stimuli causing PAH, some may act only by stimulating survivin. This may be particularly relevant to disease states, since survivin expression is not only regulated in a cell cycle–dependent manner but is also under the influence of many factors, including hypoxia and ubiquitous transcription factors such as NF-κB (10).
In several tumor series, presence of survivin correlated with a lower apoptotic index in vivo and shorter overall patient survival (15, 16). Whether these characteristics apply to iPAH is of great interest. There is considerable dissimilarity among patients with PAH regarding disease progression rates and treatment responses. Whether the level of survivin expression in pulmonary vessels reflects the potential for disease progression remains to be tested.
The use of molecular antagonists of survivin to increase cell death might hold therapeutic potential, most notably for tumors (11). Because survivin is expressed chiefly in growing tissues, limited toxicity for normal tissues would be expected. Previous in vivo results published in the JCI are consistent with this possibility, showing selective inhibition of tumor growth in mice treated with a survivin mutant adenovirus (17). Survivin antagonists hold appeal in the treatment of PAH, as they may work in the various forms of PAH, despite differences in pathogenic mechanisms. However, the view that survivin is expressed only in cancers has been challenged by many studies. Survivin expression has been documented in adult quiescent cells, including several cell types in the central nervous system, circulating neutrophils and lymphocytes, hematopoietic stem cells, hepatocytes, and intestinal crypt cells (11, 13, 18). Administration of survivin antagonists via an intratracheal route may limit untoward systemic effects but may not be devoid of toxicity to airways and alveolar epithelial cells or to ECs. Thus, whether survivin antagonists can be safely administered to PAH patients without affecting systemic organs and lung cell types other than PASMCs will have to be extensively studied before these agents are considered for therapeutic purposes.
See the related article beginning on page 1479.
Nonstandard abbreviations used: aPAH, PAH associated with underlying diseases; BMP, bone morphogenic protein; BMPRII, bone morphogenic protein receptor type 2; ET-1, endothelin-1; 5-HHT, serotonin transporter; 5-HT, serotonin; iPAH, idiopathic PAH; PAH, pulmonary arterial hypertension; PASMC, pulmonary artery SMC.
Conflict of interest: The author has declared that no conflict of interest exists.