Research

Introduction

The long-term goal of our research is to identify and characterize novel ECM components of the blood vessel wall. We currently focus on the molecular mechanisms by which fibulins establish vessel structural integrity (i.e. formation of elastic fibers), modulate intercellular signaling, and affect cellular functions. We also study microenvironment of adult vascular stem cells by utilizing various mouse models with altered levels of fibulin proteins.

Fibulins

We are particularly interested in Class II fibulins, which consisted of four members and are characterized by short calcium binding-EGF like motifs. Fibulins-3, -4 and -5 are involved in different aspects of elastic fiber formation. Fibulin-7 is the newest member and suggested to be involved in tooth development.

Fibulin-5 and Regeneration of Elastic Fibers

Elastic fibers are formed during late embryogenesis and continue to develop in early postnatal life. Once elastic fibers are formed, they provide life-long support against mechanical strain by conferring elastic and recoiling properties to tissues and organs. Congenital diseases resulting from abnormal synthesis of elastic fiber components or accelerated destruction of elastic fibers leads to pathological conditions known as cutis laxa (loose skin), tortuous aorta, pulmonary emphysema, and pelvic organ prolapse.

Fibulin-5 is essential for elastic fiber formation in vitro and in vivo. A robust elastogenic activity is demonstrated in human foreskin fibroblasts culture incubated with recombinant fibulin-5 (Figure 1). We have shown that fibulin-5 binds the monomer form of elastin, microfibrillar scaffold and cross-linking enzymes, thereby facilitating elastic fiber assembly.


Mice deficient for the fibulin-5 gene develop systemic elastic fiber defects despite normal expression of elastic fiber-associated proteins, including elastin, fibrillin-1 and cross-linking enzymes. Administration of fibulin-5 by adenovirus-mediated gene transfer induces de novo synthesis of elastic fibers in mutant mice (Figure 2). We are unveiling the molecular mechanism of elastic fiber formation by identifying novel components involved in this process.