Michael Simons, MD, FACC, FAHA

The principle research themes in the lab are the mechanisms of vascular homeos and growth factor signaling. These process are investigated at all levels, including in vitro signaling studies, in vivo mouse transgenic and knock-out models and translational studies in larger animal models and early phase clinical trials.

There are 3 major areas of research in my lab:

1. Regulation of arterial development and branching morphogenesis The purpose of these studies is to elucidate molecular pathways leading to arterial specification of the endothelium and formation of arterial vasculature. We have recently demonstrated that knockout of synectin, a PDZ protein involved in endosomal trafficking of a number of TK receptor complexes leads to selective reduction in arterial morphogenesis and vascular branching (Chittenden et al Dev Cell, 2006). We have now demonstrated that synectin controls retrograde trafficking of VEGF-R2 containing endosomes via its binding to myosin-VI. Interestingly, myosin-VI knockout in mice or knockdown in zebrafish leads to the same arteriopenic phenotype. This abnormal receptor trafficking results in impaired activation of one of VEGF-R2 signaling pathways that appears to be crucial for arterial specification. Rescue of this aspect of VEGF signaling fully restores arterial morphogenesis not only in synectin null or myosin-VI null mice but in other models of poor arterial development. Thus, this may be the critical pathways specifying arterial formation. Funding: NHLBI (2007-2025)
2. Regulation of vascular maintenance. It has not been realized until recently that maintenance of vascular integrity is an active process requiring an ongoing signaling. We have been able to demonstrate that suppression of basal FGF signaling in endothelial cells results in loss of cell-cell contacts and loss of endothelium from the vascular wall (Murakami et al. JCI 2008). The molecular events involved include FGF regulation of VE-cadherin phosphorylation and suppression of local Src activation. Current efforts are focused on characterization of the FGF signaling-VE-cadherin link and elucidation of other pathways regulating VE-cadherin maintenance t the plasma cell membrane Funding: NHLBI (2008-2025).
3. Syndecan-2 signaling. Over the years my lab has demonstrated that syndecan-2 (Sdc2) plays a critical role in regulation of VEGF signaling and, in particular, the vascular permeability cascade. Mice with a deletion of the Sdc2 gene do not develop edema following tissue injury or secondary to an inflammatory response. In addition, Sdc2 in involved in regulation of VISTA-based activation of monocytes. A blockade of Sdc2 on monocytes results in decreased local and systemic inflammatory response in tissue injury settings such as stroke or myocardial infarction. The alb is developing human therapeutics based on these findings. Funding: NHLBI (2008-2025) and Open Philantrophy Foundation

In addition, other emerging projects in the lab include: