Endothelial cells (EC) mount distinct cellular responses to signaling inputs as primitive vessel networks expand via sprouting angiogenesis. This heterogeneity in cellular behaviors is achieved by differential signaling of key pathways such as VEGF-A and BMP. Underlying differences in signaling is EC heterogeneity at the level of gene expression and post-translational protein regulation. We define EC heterogeneity as distinct cellular behaviors in response to either molecular or mechanical signals, accompanied by variation in expression profiles and regulation of key pathway regulators. My lab has contributed to understanding how VEGF-A and BMP signaling contribute to EC heterogeneity and how Notch co-ordinates these pathways. Heterogeneity is lost as vessels respond to flow- mediated signals and remodel, and vessels ?reactivate? to sprout and form new networks during physiological wound healing. These observations lead to several questions whose answers will impact our basic understanding of blood vessel formation and function, and help understand cardiovascular diseases. Our goals going forward are to investigate developmental EC heterogeneity, to examine how heterogeneity is lost as vessels remodel to homeostasis, and to test the novel hypothesis that reactivation of developmental EC heterogeneity contributes to wound healing angiogenesis. We will use both models and tools that we've developed and successfully used to date, and also incorporate new state-of-the-art approaches and tools to extend the impact of our findings beyond early sprouting angiogenesis. Our over-arching hypothesis is that EC heterogeneity is promoted by low or absent flow-induced shear stress, and repressed when shear stress reaches a critical threshold(s) by transitions in regulation of signaling pathways. We further posit that wound healing angiogenesis is promoted by reduced shear stress downstream inflammation-induced tortuous vessel formation. We will focus on the respective roles of VEGF- A and BMP signaling in these processes. This new knowledge will fill critical gaps in our knowledge of how EC achieve this remarkable transition from heterogeneous outputs to homeostasis to reactivation. This new knowledge, in turn, will allow us and others to examine more precisely how dysregulation of EC transitions contributes to disease.

Public Health Relevance

Differential regulation of growth factor signaling in endothelial cells that line blood vessels is important for formation of blood vessel networks during embryonic development. Once blood vessels form, this differential regulation is equalized among endothelial cells and reduced so vessels can function as conduits for oxygen and nutrients. However, vessels can respond quickly to reinitiate differential signaling and form new vessel networks in some situations, for example during wound healing. This work will study those states, ask how endothelial cells respond appropriately, and determine what changes during the transition periods lead to different signaling outcomes, thus setting the stage for new ideas for therapeutic interventions in diseases involving blood vessels.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Unknown (R35)
Project #
1R35HL139950-01
Application #
9433414
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Gao, Yunling
Project Start
2018-01-01
Project End
2024-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Rojas, Juan D; Papadopoulou, Virginie; Czernuszewicz, Tomasz et al. (2018) Ultrasound Measurement of Vascular Density to Evaluate Response to Anti-angiogenic Therapy in Renal Cell Carcinoma. IEEE Trans Biomed Eng :
Arreola, Alexandra; Payne, Laura Beth; Julian, Morgan H et al. (2018) Von Hippel-Lindau mutations disrupt vascular patterning and maturation via Notch. JCI Insight 3:
Rojas, Juan D; Lin, Fanglue; Chiang, Yun-Chen et al. (2018) Ultrasound Molecular Imaging of VEGFR-2 in Clear-Cell Renal Cell Carcinoma Tracks Disease Response to Antiangiogenic and Notch-Inhibition Therapy. Theranostics 8:141-155
Wylie, Lyndsay A; Mouillesseaux, Kevin P; Chong, Diana C et al. (2018) Developmental SMAD6 loss leads to blood vessel hemorrhage and disrupted endothelial cell junctions. Dev Biol 442:199-209