Educational paper. Connective tissue disorders with vascular involvement: from gene to therapy.

Lut Van Laer,Dorien Proost,Bart L Loeys

doi:10.1007/s00431-012-1773-x

Abstract

Heritable connective tissue diseases comprise a heterogeneous group of multisystemic disorders that are characterized by significant morbidity and mortality. These disorders do not merely result from defects in the amount or structure of one of the components of the extracellular matrix, as the extracellular matrix also serves other functions, including sequestration of cytokines, such as transforming growth factor beta (TGFβ). Indeed, disturbed TGFβ signaling was demonstrated in several heritable connective tissue diseases, including syndromic forms such as Marfan or Loeys-Dietz syndrome and non-syndromic presentations of thoracic aortic aneurysm/dissection. Because of these findings, new therapeutic targets have been unveiled, leading to the initiation of large clinical trials with angiotensin II type 1 receptor antagonists that also have an inhibiting effect on TGFβ signaling. Here, we present an overview of the clinical characteristics, the molecular findings, and the therapeutic strategies for the currently known syndromic and non-syndromic forms of thoracic aortic aneurysm/dissection.

Highlights

The extracellular matrix (ECM) is a highly organized multimolecular structure that is indispensable for the normal functioning of organ systems
Most genes shown to be implicated in Heritable connective tissue diseases (HCTD) encode structural connective tissue proteins, such as collagens, fibrillin and fibronectin, or enzymes involved in the biosynthesis or processing of those proteins
After the finding of increased TGFβ signaling in a Marfan syndrome (MFS) mouse model [36], the discovery that mutations in TGFBR1/2 were the cause of another aneurysmal syndrome and the fact that these loss-of-function mutations led to a paradoxical activation of TGFβ signaling provided further proof for an important role of TGFβ signaling in aneurysma development [29]

Summary

Introduction

The extracellular matrix (ECM) is a highly organized multimolecular structure that is indispensable for the normal functioning of organ systems. The current perception of the ECM is that of a complex network that, besides its mechanical role in providing strength and support to the tissues, acts as an important reservoir for cytokines and growth factors implicated in cellular proliferation, differentiation, migration, and survival and has an important regulatory function in the development and homeostasis of body organs and tissues [43]. For these HCTD, we would like to refer to other recent reviews [9, 13, 33, 49]

Marfan syndrome

Arterial tortuosity syndrome

Cutis laxa