Sugar Rush: How Diabetes Leads to Vascular Disease
Diabetes is a devastating disease affecting millions worldwide. Vascular complications are a major cause of morbidity and mortality in the diabetic population. Although much effort has been placed in examining mechanisms of endothelial dysfunction in diabetes, vascular smooth muscle complications are understudied. The L-type Ca2+ channel CaV1.2 plays key roles in vascular smooth muscle excitability, muscle contraction and gene expression. Exaggerated CaV1.2 activity has been implicated in the chain of events contributing to hyperglycemia-induced vascular complications during diabetes, but the mechanisms for this remains the subject of investigation. In this webinar, Dr. Navedo discusses new data describing a previously unappreciated pathway that gets activated by hyperglycemic conditions and contributes to changes in vascular function. He presents evidence that activation of this pathway can contribute to changes in vascular smooth muscle CaV1.2 activity and vascular reactivity in animal models of diabetes and diabetic patients. The exquisite detail of the dissected signaling pathway and the link to vascular complications was made possible by the implementation of a multiscale approach that examines changes from the biochemical level to single-molecule biophysics to changes in cerebral blood flow and systemic blood pressure. For this, Dr. Navedo uses 1) sophisticated biochemistry to examine protein abundance and phosphorylation state of proteins, 2) electrophysiology to examine changes in ion channel activity, 3) super-resolution microscopy and PLA assay to define the spatial distribution of proteins, 4) pressure myography to examine effect of treatments on myogenic tone, 4) radio telemetry to measure blood pressure and 5) Laser Speckle imaging to explore the consequences of different treatments in blood flow regulation. With this approach, the research team can provide a comprehensive examination of hyperglycemia and diabetic effects in vascular smooth muscle that extend from the single-molecule to the whole animal level.
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Sugar Rush: How Diabetes Leads to Vascular Disease
- 1. Manuel F. Navedo, Ph.D Department of Pharmacology University of California, Davis Sugar Rush: How Diabetes Leads to Vascular Disease
- 3. Sugar Rush: How Diabetes Leads to Vascular Disease Manuel F. Navedo, PhD Department of Pharmacology University of California Davis Scintica: INSTRUMENTATION Webinar M&M Lab – @mf_navedo on
- 4. Goals of the webinar! • Understand what is arterial (myogenic) tone and the role of different ion channels involved • Appreciate effects of hyperglycemia on CaV1.2 channel activity and vascular reactivity • Describe mechanisms by which hyperglycemia modulates CaV1.2 channel activity and vascular reactivity from single-molecule events to whole-body physiology • Implement a multiscale approach for any given research program
- 5. Diabetes and Vascular Complications • World Health Organization estimates that 350 million people worldwide have diabetes • Major economic impact ($327 billions in USA; ∼$10K in individual medical cost) and burden to the health system • Major impact on the vasculature – endothelial dysfunction • Vascular complications are major causes of morbidity and mortality • Retinopathy • Renal failure • Ischemic limb • Hypertension • Reduced cerebral blood flow and cognitive impairment • Emerging evidence of vascular smooth muscle complications contributing to altered myogenic tone, reduced organ BF and increased BP ADA Diabetes Care 41, 917-928
- 6. The Myogenic Response Intravascular pressure Membrane depolarization (TRPC, TRPP, TRPM channels activation) L-type Ca2+ channel CaV1.2 Global [Ca2+]i Contraction Knot & Nelson J Physiol 508: 199 Hyperglycemia/diabetes • Intrinsic property of vascular smooth muscle • William Bayliss - J Physiol 1902
- 7. Use of a Multiscale Approach to Examine Vascular Complications in Diabetic Hyperglycemia mRNA/ protein expression phosphorylation events microscopy • Biochemistry • Electrophysiology • Multiple imaging approaches • In silico modeling • Pressure myography • Radio telemetry • Laser Speckle imaging whole body organ vessel isolated cells ion channels/ signaling proteins
- 8. What we have learned about how diabetic hyperglycemia regulates vascular function? elevated glucose (hyperglycemia) Navedo et al AJP 2010 Nystoriak et al Science Signaling 2017 P contraction gene expression Syed et al JCI 2019 ATP Prada et al eLife 2019 Nystoriak et al Circ Res 2014 glucose glucose metabolism NUC production NUC How glucose stimulates a specific PKA pool to potentiate CaV1.2 activity/contraction? What holds all these proteins together? AKAP5
- 9. An AKAP is Necessary for Glucose/NF546-induced cAMP Synthesis in Human Vascular Smooth Muscle cultured smooth muscle Prada et al Nature Communications 2020 Syed et al JCI 2019
- 10. AKAP5 is Necessary for Glucose/NF546-induced cAMP Synthesis cultured smooth muscle AC5 is also necessary for glucose/NF546-induced cAMP synthesis!!! Prada et al Nature Communications 2020
- 11. Key Roles for AKAP5 and AC5 in P2Y11-mediated Stimulation of L- type Ca2+ Channel Activity and Vasoconstriction (ex vivo) patch clamp Global Ca2+ using spinning disk confocal Prada et al Nature Communications 2020
- 12. Key Roles for AKAP5 in P2Y11-dependent Vasoconstriction (in vivo) intravital imaging Laser Speckle Imaging Prada et al Nature Communications 2020
- 13. Other Applications for Laser Speckle Imaging blood flow and diameter in mesenteric arteries in response to angII Sexual dimorphic response to adrenergic stimulation Reddy et al unpublished • Applied to different animal models • Progression of vascular disease • Pre-clinical studies
- 14. Audience Poll
- 15. Nystoriak et al Circulation Research 2014 AKAP5 Ablation Prevents Elevated Blood Pressure in Diabetes radio telemetry for blood pressure measurements LFD HFD diet-induced diabetes
- 16. AKAP5 Closely Associates with P2Y11, AC5 and CaV1.2 Super-resolution Airy scan confocal microscopy (120 nm lateral resolution Super-resolution ground state depletion (20-40 nm lateral resolution) Prada et al Nature Communications 2020
- 17. AKAP5 Associates with P2Y11, AC5, PKA and CaV1.2 in Human Vascular Smooth Muscle Proximity Ligation Assay Prada et al Nature Communications 2020
- 18. AKAP5 Fosters the P2Y11, AC5, PKA and CaV1.2 Nanocomplex Prada et al Nature Communications 2020
- 19. PDE Inhibition Restores cAMP Signal but not Vasoconstriction in AKAP5-/- Cells/Tissue AKAP5 is still essential for glucose/NF546- induced vasoconstriction! Prada et al Nature Communications 2020
- 20. Conclusions Nystoriak et al Science Signaling 2017 Syed et al JCI 2019 Prada et al eLife 2019 Nystoriak et al Circ Res 2014 glucose metabolism P contraction gene expression ATP glucose NUC production NUC Prada et al Nature Communications 2020 • Novel nanocomplex: AKAP5/P2Y11/AC5/PKA/CaV1.2 • Regulates cAMP signaling, CaV1.2 activity and vascular reactivity in hyperglycemia • Potential involvement in vascular complications during diabetes • Multiscale approach to uncover mechanisms of vascular complications in diabetic hyperglycemia
- 21. Acknowledgements R01HL098200 R01HL121059 R01HL149127 Madeline Nieves-Cintron, PhD PI M&M Lab Maria Prada Arsalan Syed Raghu Reddy Victor FloresMiguel Martin Aragon Baudel Victoria Ramer Collaborators UC Davis Johannes W. Hell Yang K. Xiang Eamonn J. Dickson Ele Grandi Nipavan Chiamvimonvat Luis F. Santana UN Reno Sean M. Ward UW Seattle John D. Scott June Hong Navid Singhrao
- 22. Thank you!!!
- 23. To ask a question, click the Q&A Button, type your question and click send. Any questions that are not addressed during the live webinar will be answered following the event. Please indicate whom you want to address your question. Thank you for participating! Q&A SESSION: Manuel F. Navedo, Ph.D Department of Pharmacology University of California, Davis