Biomedical Engineering Reference
In-Depth Information
increases TGF-
b
production in cultured vascular SMCs (93), a potential
mechanism by which increased flow and
=
or pressure might result in vascu-
lar remodeling. In addition, TGF-
b
1 stimulates the production of ET-1 in
bovine pulmonary artery endothelial ceils and in isolated perfused rat
lungs, thereby suggesting alternative mechanism of pulmonary remodeling
(94).
VI. PATHOGENETIC MECHANISMS
A. Genetic Factors
Current understanding of the pathogenesis of pulmonary hypertension has
improved dramatically with the identification of germline mutations in
patients with familial primary pulmonary hypertension (FPPH). Genetic
analysis in these individuals has contributed to identify genes that are crucial
for the pathogenesis of pulmonary hypertension, not only in the inherited
form but also in sporadic forms and those associated with other disease
conditions.
1. Bone Morphogenetic Protein Receptor
In the year 2000, two groups almost simultaneously reported that about
50% of individuals with FPPH had mutations in the gene encoding for
the bone morphogenetic protein receptor type II (BMPR2) (95,96). This is
a receptor for a family of secreted growth factors named bone morpho-
genetic proteins (BMPs), which are part of the TGF-
b
family (84). Origin-
ally identified as proteins regulating growth and differentiation of bone
and cartilage, BMPs also regulate growth, differentiation, and apoptosis
of various cell types (97). Mutations identified in patients with FPPH inter-
rupt the BMP-mediated signaling pathways, resulting in a predisposition to
proliferation of SMCs in pulmonary arteries (98). Mutations of the BMPR2
gene have also been identified in patients with sporadic PPH (99). Whereas
some of these cases represent patients with an unidentified inherited form of
the disease (99,100), in others the mutation appears de novo (99). Mutations
in the BMPR2 gene have also been identified in pulmonary arterial hyper-
tension associated with anorexigen use (101). These studies indicate that
the TGF-
b
family plays a critical role in the maintenance of pulmonary ves-
sel integrity, and that alterations in the TGF
=
BMP signaling pathway are
crucial for the development of pulmonary hypertension. Interestingly,
asymptomatic members of FPPH families that carry mutations in the
PPH gene may develop pulmonary hypertension during exercise (102). This
suggests that alterations in the PPH gene are associated with phenotypical
changes, either an abnormal vascular reactivity or subclinical vascular
lesions, even in subjects who do not manifest the full clinical picture of
severe pulmonary hypertension.
