APS Annual Meeting at Experimental Biology



Intracellular Ca²⁺ in the Macro- and Microcirculation – Diversity of Function

Symposium — Tuesday, April 5, 2022 — 3:30 PM - 5:00 PM — Convention Center, Room 201C
Cardiovascular Section — Chair: Michael Sturek — Co-Chair: Madeline Nieves-Cintron

The obvious size difference in the macro- and microcirculation is accompanied by differences in vasomotor responsiveness to hormones and metabolites. The macrovasculature (conduit arteries) are the major location of atherosclerosis, while the microcirculation is the major regulator of blood flow. Less well studied are the Ca2+ signaling mechanisms underlying the different pathophysiology. The theme is the diversity of regulation and function, which can be further complicated by differences in vascular bed, species, gender, and disease status.

Sturek will introduce the session and discuss vascular smooth muscle (VSM) from coronary conduit arteries. The SR Ca2+ store transitions from increased Ca2+ content in early atherosclerosis with proliferation of VSM. Decreased SR Ca2+ content occurs later in atherosclerosis when Ca2+ is transported out of the cell to form hydroxyapatite crystals in the extracellular matrix. This biphasic transition paradigm has been shown in pig and human coronary arteries. Ca2+ sparks activation of KCa channels is not shown in VSM from conduit coronary arteries, but is seen in VSM from coronary microvessels. The spatial association of lysosomes and SR imply a transfer of Ca2+ between stores, which could facilitate vesicular secretion of hydroxyapatite.

Thakore will show exquisitely fine control of Ca2+ sparks by Ca2+ release from lysosomal Ca2+ stores via TRPML channels to trigger Ca2+-induced Ca2+ release through ryanodine receptors from neighboring SR Ca2+ stores. The stable localization of lysosomal Ca2+ stores is shown in contractile smooth muscle in mouse cerebral microvessels. The Ca2+ sparks-KCa channel activation-hyperpolarization and relaxation paradigm is central to the function of microvessels. Dedifferentiation of the VSM cells as they proliferate in culture induces phenomenal trafficking of lysosomal stores in the cells, thereby uncoupling Ca2+ sparks to KCa activation.

Li will feature the role for TRPML channels in coronary artery calcification. Mice with smooth muscle-specific acid ceramidase fed high doses of vitamin D develop severe arterial medial calcification or aorta and coronary arteries. Culturing coronary artery VSM elicits dedifferentiation and small extracellular vesicle release into the media and calcification. Direct patch clamping of lysosomes shows inhibition of TRPML channels in the acid ceramidase knockouts, thereby decreasing the interaction with multivesicular bodies. These provocative findings again reinforce the diverse regulation and function of Ca2+ stores and channels in different VSM phenotypes.

Nieves-Cintron will highlight the profound effects of diabetes (hyperglycemia) on sarcolemmal Ca2+ channels in resistance arteries. Effects of hyperglycemia on the SR Ca2+ store are variable, but the typical effect is to inhibit Ca2+ sparks-KCa channel activation. In hyperglycemic conditions glucose entering the cells also can produce nucleotides locally that couple to AKAP5 to increase cAMP and activate Cav1.2 channels. Transcriptional regulation patterns result in a feedforward mechanism perpetuating Ca2+ channel activation and microvascular constriction.

This symposium should be of interest to the APS Cardiovascular, Environmental & Exercise, and Cell & Molecular sections. These speakers represent a variety of perspectives, including animal models, in vitro models, and human tissue. Both genders, a variety of career stages, and ethnicities should promote diversity.

Speakers

  • Introduction
    Madeline Nieves-Cintron — Pharmacology, University of California at Davis
    3:30 PM - 3:35 PM

  • Sarcoplasmic Reticulum and Endo/Lysosomal Ca2+ Store Cross-Talk in Coronary Macrovasculature
    Michael Sturek — Anatomy, Cell Biology, & Physiology, Indiana University School of Medicine
    3:35 PM - 3:55 PM

  • TRPML Channels Trigger Ca2+ Sparks in Vascular Smooth Muscle Cells
    Pratish Thakore — Pharmacology, University of Nevada, Reno
    3:55 PM - 4:15 PM

  • TRPML Channels in Coronary Vascular Phenotypic Modulation and Calcification
    Pin-Lan Li — Pharmacology and Toxicology, Virginia Commonwealth University
    4:15 PM - 4:35 PM

  • Local Ca2+ Channel Regulation of Vascular Smooth Muscle in Diabetes
    Madeline Nieves-Cintron — Pharmacology, University of California at Davis
    4:35 PM - 4:55 PM

  • Closing Remarks
    Michael Sturek — Anatomy, Cell Biology, & Physiology, Indiana University School of Medicine
    4:55 PM - 5:00 PM




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