Acute Aortic Disease.. - Index of

116 Milewicz et al.
assembly of a heteromeric receptor complex of Type I and Type II receptors,
within which the TGF-β receptor II transphosphorylates and activates the Type I
receptor. Cellular signaling after TGF-β binding and receptor activation is regulated
through several pathways, of which the most thoroughly investigated pathway
is the Smad pathway. The TGF-β Type I receptor signals through Smad2 and
Smad3. Phosphorylation of Smad2 and Smad3 by the TGF-β Type I receptor
increases the affinity of these for Smad4, leading to the translocation of the heteromeric
Smad complex from the cytoplasm into the nucleus and the subsequent
transcription of downstream effector genes (Fig. 10).
Current research suggests a broad role for dysregulated TGF-β signaling in
aortic disease pathogenesis, either via inappropriate release of bioactive TGF-β,
as observed in MFS, or by disruptions in signaling due to mutations in the receptors
for TGF-β observed in familial TAAD, LDS, as well as a subset of MFS. Analysis of
the hypomorphic FBN1 mouse model of MFS first provided a connecting pathway
between decreased formation of microfibrils, TGF-β, and the manifestations of MFS.
The bioavailability of active TGF-β ligand is tightly regulated and dependent on its
release from a large latent complex to which TGF-β is noncovalently associated with
its propeptide fragment, the latency-associated peptide, and covalently linked to
latent TGF-β-binding protein 1 (LTBP-1) (Fig. 10). This complex associates with
fibrillin-1-containing extracellular microfibrils and mutations in fibrillin-1 lead to
diminished amounts of microfibrils in the extracellular matrix. Studies of fibrillin-1
deficient mice demonstrated increased active TGF-β in tissues when compared with
wild type mice, suggesting diminished microfibrils increased the bioavailability of
active TGF-β in tissues (53). Furthermore, antagonism of active TGF-β prevented the
pulmonary parenchymal and mitral valve abnormalities observed in these mice,
suggesting a cause and effect relationship (53,54). Interestingly, a recent study has
also shown that aortic aneurysm in a mouse model of MFS is indeed associated
with increased TGF-β signaling and can be ameliorated by the angiotensin II Type 1
receptor (AT1) blocker, losartan (55). Prior evidence suggests crosstalk between the
TGF-β and angiotensin II signaling pathways; however, the mechanism by which
losartan acts to prevent aortic aneurysms remains to be elucidated.
The mechanism of enhanced TGF-β signaling implicated in MFS manifestations
caused by FBN1 mutations, while difficult to reconcile with the putatively
kinase-inactivating TGFBR1 and TGFBR2 mutations identified in LDS, appears
to be the basis of aortic disease in both these syndromes (21). Surprisingly, tissues
from these affected individuals with TGFBR2 mutations showed increased expression
of both collagen and connective tissue growth factor, as well as nuclear
enrichment of phosphorylated Smad2, suggesting increased TGF-β signaling in
these tissues.
This theme of activation of TGF-β signaling is also observed in familial
TAAD. Transient transfection experiments to measure cellular responsiveness to
TGF-β mediated by wild type or mutant (R460C and R460H) TGFBR2 confirmed
our structural modeling studies indicating that both the R460C and R460H mutations
diminish downstream signaling in response to TGF-β. This was followed