CWRU Cardiovascular Research Institute

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Research Synopsis

The vascular system is responsible for the delivery of nutrients and oxygen to all our bodies and is the first organ system to develop. Vessels form through two mechanisms: 1) vasculogenesis imparts the generation of endothelial progenitors and the de novo formation of vessels; and 2) angiogenesis is responsible for the growth and maturation of vessels by various processes including, sprouting, ECM production, and recruitment of supporting mural cells. Both of these processes are regulated by the transcriptional protein complex Hypoxia Inducible Factor (HIF). HIF is and essential oxygen sensor that activates an adaptive response to compensate hypoxia and is known to regulate various steps in vascular development and pathologies. Abrogation of the ARNT (arylhydrocarbon receptor nuclear translocator) subunit of the HIF heterodimer results in embryonic lethality by 10.5 days postcoitum (dpc) associated with various cardiovascular defects. Using a mouse embryonic stem cell differentiation system, we have determined that ARNT is required for the development of hemangioblasts, a critical cardiovascular stem cell progenitor. We are currently investigating the environmental influence of hypoxia on the behavior of endothelial cells by examining how it directs the temporal activity of VEGF signals. We are exploring similar analysis using in vivo models and HIF’s requirements in vascular smooth muscle cells. We are interested in defining the role of endothelial-HIF in stem cell niches and are currently focusing on the bone marrow’s vascular stem cell niche.

Slide 1

Focus 1: Examine how hypoxia promotes the emergence of cardiovascular progenitor cells and directs their lineage specification by defining the connection between Notch and HIF pathways.

Slide 2

Focus 2: Examine how hypoxic signals from the bone marrow vascular niche regulate the maintenance of hematopoietic stem
cells (HSC) and proangiogenic progenitor cells (PPC) and contribute to its regeneration following pathological stress.

Slide 3

Focus 3: Examine how hypoxia promotes specific stages of
vascular development and sustains postnatal angiogenesis.

Slide 4

Focus 4: Examine the requirements for ARNT during vascular development using mouse genetic models.

Contact Information

Iris S. and Bert L. Wolstein Research   Building
2103 Cornell Road
Office: WRB 4-532
Lab: WRB 4-404A

216-368-2036 (Phone)
216-368-7290 (Fax)
diana.ramirez@case.edu