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Review
. 2014:802:107-27.
doi: 10.1007/978-94-007-7893-1_8.

Connective tissue disorders and cardiovascular complications: the indomitable role of transforming growth factor-beta signaling

Jason B Wheeler  1 , John S Ikonomidis, Jeffrey A Jones
Affiliations
Review

Connective tissue disorders and cardiovascular complications: the indomitable role of transforming growth factor-beta signaling

Jason B Wheeler et al. Adv Exp Med Biol. 2014.

Abstract

Marfan Syndrome (MFS) and Loeys-Dietz Syndrome (LDS) represent heritable connective tissue disorders that cosegregate with a similar pattern of cardiovascular defects (thoracic aortic aneurysm, mitral valve prolapse/regurgitation, and aortic root dilatation with regurgitation). This pattern of cardiovascular defects appears to be expressed along a spectrum of severity in many heritable connective tissue disorders and raises suspicion of a relationship between the normal development of connective tissues and the cardiovascular system. Given the evidence of increased transforming growth factor-beta (TGF-β) signaling in MFS and LDS, this signaling pathway may represent the common link in this relationship. To further explore this hypothetical link, this chapter will review the TGF-β signaling pathway, heritable connective tissue syndromes related to TGF-β receptor (TGFBR) mutations, and discuss the pathogenic contribution of TGF-β to these syndromes with a primary focus on the cardiovascular system.

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Figures

FIGURE 5.1
FIGURE 5.1
Canonical, Noncanonical, and Endoglin/ALK-1 signaling pathways. Both Canonical and Endoglin/ALK-1 TGF-Beta signaling is mediated by the phosphorylation of distinct receptor Smad proteins. Nuclear translocation requires Co-Smad binding in both pathways. Inside the nucleus, R- and Co-Smads form a complex with transcription factors to either repress or activate TGF-Beta related gene expression. The noncanonical pathway is mediated by TGFBRI, TRAF6, and TAK1 and results in the phosphorylation of MAPKs such as Erk1/2, JNK, and p38. These MAPKs can re-enter the Smad-dependent pathway through phosphorylation or mediate downstream signaling through other Smad-independent pathways. The lightning bolts represent mutations to the indicated proteins causative of the syndromes listed in red.
FIGURE 5.2
FIGURE 5.2
Known heritable connective tissue disorders with cardiovascular involvement that associate with gene mutations related to TGF-Beta signaling. These disorders are arranged based on their increasing level of either connective tissue or cardiovascular involvement and notably share a spectrum of common symptoms, which supports their related pathophysiology.
See this image and copyright information in PMC

References

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