KLF15, TGFb1 and smooth muscle cell biology

Brigham And Women'S Hospital, Boston MA

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Abstract

[unreadable] DESCRIPTION (provided by applicant): The vascular smooth muscle cell (VSMC) is one of the principal cellular constituents of the blood vessel wall. This cell type is involved in important functions such as regulation of blood pressure (through contraction and relaxation) and formation of mature blood vessels. In response to injury to the vessel wall, the VSMC undergoes a change in phenotype characterized by reduced levels of contractile proteins, enhanced proliferation and migration, and elaboration of extracellular matrix components. These features are instrumental in the development of obstructive vascular diseases which ultimately leads clinical entities such as myocardial infarction, stroke, and ischemic limbs. As such identification of factors that regulate SMC growth and development is of critical importance. Members of the Kruppel-like family of factors are transcription factors which are involved in regulating cellular growth and differentiation. We identified a member of this family termed KLF15 which is highly expressed in blood vessels in vivo. KLF15 expression correlates with the differentiated and quiescent SMC phenotype both in vitro and in vivo. Overexpression and loss-of-function studies support a role for KLF15 in the regulation of SMC gene expression, growth, response to injury, and vasoreactivity. These observations have led us to the central hypothesis that KLF15 is an important regulator of SMC differentiation, growth, and function. In AIM 1 of this proposal we explore the mechanistic basis for KLF15's ability to induce SMC gene expression. In AIM2, we examine the role of KLF15 in the TGFb1 mediated induction of SMC genes. Finally, in AIM 3, we assess the developmental and functional consequences of KLF15 deficiency on SMC development and on blood vessel function (response to injury and vasoreactivity). Taken together these data will provide insight regarding the role of KLF15 in SMC biology. The results of these studies are of considerable scientific interest and may also serve as the basis of novel therapeutic strategies to develop mature blood vessels or to modulate the SMCs response to injury. [unreadable] [unreadable]