Endothelial dysfunction is a key component of the pathogenesis of many important diseases of humans and animals.  These include atherosclerosis and its association with coronary artery disease and stroke, diabetes, systemic hypertension and renal disease, senile dementia, and pulmonary vascular disease and heart failure.  Over the past several years, our laboratory has been investigating endothelial biology in relationship to the accumulation of lipids in the arterial wall, the pathogenesis of pulmonary hypertension and the mechanisms of intimal proliferation in restenosis after angioplasty. Among the unifying concepts in vascular remodeling resulting from all these syndromes is the role of TGFß family signaling in vascular biology.

 

The TGFß family of cytokines includes a diverse group of locally acting signaling molecules that act through related local release and receptor mechanisms to direct pre and post natal differentiation of tissues.  Among the mediators in this system are TFG-ß1, -ß2 and -ß3, activins, Bone Morphogenetic proteins (BMPs), nodal, and GDF’s.  These cytokines act through heterodimeric pairs of transmembrane receptors to phosphorylate specific members of a second messenger family known as smads.  Complexes of smads are translocated to the nucleus where they promote or regulate transcription that is cell type and cofactor dependant.  The diversity of TGFß cytokines, their ability to interact with multiple receptor combinations that can be additionally modified by their location in membrane microdomains as well as post signaling modifications in the second messenger systems allows exquisite control of local responses.  In addition to their potential to be secreted by several cell types, TGFß cytokines are sequestered in extracellular matrix in a latent form that can be locally activated by several mechanisms that allow autocrine and paracrine control of cellular responses.

 

In the vascular system, TGFß family cytokines regulate cellular proliferation in both positive and negative ways that depend on cell type and location as well as receptor interactions.  Canonical receptor activation results when a TGFß family agonist binds to a complex of two type I and two type II receptors.  The type II receptor phosphorylates the type I receptor through a kinase domain.  The phosphorylated type I receptor then catalyzes phosphorylation of a cytoplasmic agonist/receptor complex specific receptor smad (smad 2 in the case of classical TFGß signaling).  The receptor smad then forms a complex with the co-smad-4 and is translocated to the nucleus for interaction with promoter sites (figure 1).