Peripheral arterial disease (PAD) is a global problem – over 202 million people worldwide are estimated to have PAD. In the United States alone, PAD results in $21 billion in annual costs and is the leading cause of lower limb amputation. PAD arises when atherosclerotic plaques block arteries in the lower limbs, thereby limiting blood flow to the distal tissue. A promising therapeutic approach to restore distal blood flow is to stimulate the lumenal growth of the patient’s own pre-existing collateral arteries that bypass the occlusion(s) (i.e. arteriogenesis). Unfortunately, large clinical trials have had limited success to date, highlighting the critical need to better understand the basic mechanisms regulating arteriogenesis.
Arteriogenesis occurs in response to increased blood flow through the collateral arteries that bypass an occluded artery. We have recently demonstrated that arteriogenesis varies along collateral artery pathways due to differences in regional hemodynamics (Heuslein and Meisner et al. ATVB, 2015). We hypothesize that epigenetics (i.e. environmental factors that influence long-term gene expression without changing the DNA sequence) could be a predominant mechanism through which regional hemodynamics differentially regulate arteriogenesis.
In this project, we are investigating the relationship(s) between shear stress, collateral growth, inflammation, and epigenetics, using a combination of both in-vivo and in-vitro methods. Specifically, we are focusing on the epigenetic regulation of arteriogenesis by non-coding RNAs (i.e. microRNAs and long non-coding RNAs) and DNA methylation. Ultimately, these studies will enhance our fundamental understanding of arteriogenesis and may also have important bearing on the development of therapeutic strategies in patients with arterial occlusive diseases.