header image

McEnaney Lab



Location

W917 BST

Principal Investigator

Research Description

In patients with arterial occlusive disease, arteriogenesis is an adaptive process of creating collateral vessels that function to keep ischemic tissues viable.  It has been established that arteriogenesis occurs in areas of arterial interconnections which, in the case of the peripheral vasculature, are often remote from the effects of ischemia.  The inciting factors local to the developing collaterals have been elegantly demonstrated to be biomechanical forces, which become deranged after the occlusion of a conductance artery.  The collateral then remodels itself in order to normalize the biomechanical stresses it sees.  This explains why collaterals will expand diameter as well as wall thickness.  Unfortunately, it seems as though the natural equilibrium tends to halt the growth of collaterals early, when only around 40% capacitance of the occluded conductance vessel is achieved. 

Arteriogenesis represents an exciting area of potential medical therapy for unreconstructable vascular disease.  If this natural process could be pushed further, then it may provide an alternative to surgical or endovascular revascularization.  Currently, it is accepted that hemodynamic forces result in the initial stimulus for collateral formation, but early biochemical signaling pathways are not well understood.  Purinergic signaling is a tightly regulated system of receptors, extracellular purine nucleotides, and hydrolyzing enzymes, which is likely relevant in arteriogenesis but has not been studied to date.  Specifically, the lab investigates the role of purinergic signaling as an early mediator of arteriogenesis.

When exposed to mechanical forces such as shear stress or wall stress, vascular cells are known to release nucleotides in response.  Endoluminal nucleotides are able to agonize endothelial purinergic receptors, where canonical pathways lead to activation of eNOS with elaboration of nitric oxide, EDHF, in addition to mitogenic effects on the endothelium.  Nucleotides acting through purinergic receptors lead to further activities shown to be important to arteriogenesis, such as expression of adhesion molecules (ICAM-1, VCAM-1) and recruitment of inflammatory cells, as well as activation and phenotypic modulation of endothelial and vascular smooth muscle cells which leads to proliferation and migration.

Our work thus far has demonstrated that purinergic signaling through the P2Y2 purinergic receptor appears to be important for efficient collateral formation using a murine model of arterial occlusion.  In mice deficient in the P2Y2R, we observed reduced activation of resident vascular cells and reduced collateral maturation when compared to wild type mice.  We are continuing investigations to elucidate the molecular mechanisms by which purinergic signaling results in collateral growth and maturation.  The ultimate goal of this work would be to uncover potential molecular targets for medical therapeutics for patients with advanced arterial occlusive disease.

Lab Members

Publications

Xanthine oxidoreductase function contributes to normal wound healing.  Madigan MC, McEnaney RM, Shukla AJ, Hong G, Kelley EE, Tarpey MM, Gladwin M, Zuckerbraun BS, Tzeng E.  Mol Med.  2015 Apr 14;21:313-22

P2Y2 Nucleotide Receptor Mediates Arteriogenesis in a Murine Model of Hindlimb Ischemia.  McEnaney RM, Shukla A, Madigan MC, Sachdev U, Tzeng E.  J Vasc Surg. 2014; pii: S0741-5214(14)01281-6. [Epub ahead of print].  PMID: 25088742

TLR2 and TLR4 Mediate Differential Responses to Hindlimb Ischemia Through MyD88-Dependent and Independent Pathways.  Sachdev U, Cui X, McEnaney R, Wang T, Benabou K, Tzeng E.  PLoS One. 2012;7(11): e50654.  PMID: 23209800