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Pathophysiology of Pulmonary
Hypertension: Recognizing Triggers of the Disease
Marc Humbert, MD, PhD
Centre des Maladies Vasculaires Pulmonaires, Hôpital Antoine
Béclère, Université Paris-Sud, Clamart, France
It is unclear whether the various types of PAH share
a common pathogenic mechanism. Although our understanding
of the pathobiological changes underlying PAH has progressed
rapidly over the past few years, it is still impossible
to classify patients on a pathogenic basis and to define
therapeutic approach accordingly. Three factors are considered
to cause the increased pulmonary vascular resistance in
PAH: vasoconstriction, remodeling of the pulmonary vessel
wall, and thrombosis in situ. The latter two are easily
evident with light microscopy, whereas vasoconstriction
is best demonstrated by vasodilator testing. Most specialists
now agree that pulmonary vascular proliferation and remodeling,
and not vasoconstriction, is the hallmark of PAH pathogenesis.
Bone morphogenetic protein receptor 2 and related
molecules
The recent identification of a pulmonary hypertension
gene (bone morphogenetic protein receptor 2, BMPR2, a
member of the transforming growth factor beta superfamily)
provides the opportunity to develop a deeper understanding
from a molecular biology perspective. Heterogeneous germline
mutations in BMPR2 occur in approximately 60%, 25%, and
10% of patients with familial, sporadic, and fenfluramine
derivativesassociated PAH, respectively. In addition,
germline mutations in the gene coding activin-like receptor
kinase 1, another member of the transforming growth factor
beta superfamily, have been identified in patients with
hereditary hemorrhagic telangiectasia. These patients
develop severe plexiform pulmonary (or idiopathic) hypertension,
which is symptomatically indistinguishable from PPH. The
relevance of the transforming growth factor beta superfamily
in the etiology of PAH is further supported by a recent
report of endoglin germline mutation in a patient who
had hereditary hemorrhagic telangiectasia and dexfenfluramine-associated
PAH. These observations support the hypothesis that mutations
in the transforming growth factor beta superfamily may
be a trigger for pulmonary vascular remodeling.
The transforming growth factor beta superfamily is diverse,
comprising transforming growth factor beta isoforms, the
bone morphogenetic proteins, activins, and growth and
differentiation factors. A possible mechanism whereby
such a mutation could trigger remodeling is emerging from
studies on BMPR2. BMPR2 mediates its actions by binding
ligand in conjunction with a type I receptor to form a
heterodimer complex on the cell surface and subsequently
propagate an intracellular signal via Smad molecules.
As BMPR2 is involved in cell proliferation and apoptosis,
the occurrence of a mutation in this protein could result
in abnormal signaling in pulmonary artery smooth muscle
cells, leading to loss of antiproliferative or apoptotic
mechanisms. This theory is supported by the demonstration
of dysregulated growth inhibition of pulmonary artery
smooth muscle cells from patients with PPH exposed to
bone morphogenic proteins and transforming growth factor
beta. In fact, additional findings suggest that all forms
of pulmonary hypertension may be linked to defects in
the signaling pathways involved in angiogenesis, such
as angiopoietin-1 and bone morphogenetic protein receptors.
The possible involvement of the transforming growth factor
beta superfamily in the pathophysiology of PAH may have
identified a novel target for therapeutic intervention.
Modifier genes and environmental factors
As PAH develops in only 10% to 20% of individuals with
BMPR2 mutations, the contribution of other factors for
the development of PAH is undeniable. The “multiple hit”
hypothesis has been proposed whereby the combination of
a number of factors may precipitate the disease. In such
a scenario, a susceptible individual with a BMPR2 mutation
would require additional insults such as exposure to anorectic
drug before manifesting PAH. Another theory is that of
the role of modifier genes in the pathogenesis of PAH.
As recently detailed by Runo and Loyd in their Lancet
review, genes and gene products putatively implicated
in the pathogenesis of PAH include prostacyclin synthase,
nitric oxide synthase, serotonin transporter, serine elastases,
matrix metalloproteinases, voltage-gated potassium channels,
angiotensin-converting enzyme, vascular endothelial growth
factor, carbamoyl phosphate synthase, plasminogen activator
inhibitor type 1, and endothelins.
Endothelial dysfunction
Recent advances in the understanding of the molecular
mechanisms involved in PAH suggest that endothelial dysfunction
could correspond to downstream manifestations of the disease
rather than a central pathogenic mechanism. There is now
considerable evidence that endothelial dysfunction leading
to exaggerated vasoconstriction, and impaired vasodilatation
plays a key role in PAH. Interestingly, chronically impaired
production of vasodilators such as nitric oxide and prostacyclin
along with prolonged overexpression of vasoconstrictors
such as endothelin- 1 not only affect vascular tone, but
also promote vascular remodeling and therefore represent
a logical pharmacological target.
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