Carbonic Anhydrase IX Proteoglycan-Like and Intracellular Domains Mediate Pulmonary Microvascular Endothelial Cell Repair and Angiogenesis

Authors

Reece P. Stevens, University of South Alabama
Mikhail F. Alexeyev, University of South AlabamaFollow
Natalia Kozhukhar, University of South AlabamaFollow
Viktoria Pastukh, University of South Alabama
Sunita S. Paudel, University of South Alabama
Jessica Bell, University of South Alabama
Dhananjay T. Tambe, University of South AlabamaFollow
Troy Stevens, University of South AlabamaFollow
Ji Young Lee, University of South AlabamaFollow

Document Type

Article

Publication Title

American Journal of Physiology-Lung Cellular and Molecular Physiology

Abstract

The lungs of patients with acute respiratory distress syndrome (ARDS) have hyperpermeable capillaries that must undergo repair in an acidic microenvironment. Pulmonary microvascular endothelial cells (PMVECs) have an acid-resistant phenotype, in part due to carbonic anhydrase IX (CA IX). CA IX also facilitates PMVEC repair by promoting aerobic glycolysis, migration, and net- work formation. Molecular mechanisms of how CA IX performs such a wide range of functions are unknown. CA IX is composed of four domains known as the proteoglycan-like (PG), catalytic (CA), transmembrane (TM), and intracellular (IC) domains. We hypothesized that the PG and CA domains mediate PMVEC pH homeostasis and repair, and the IC domain regulates aerobic glycolysis and PI3k/Akt signaling. The functions of each CA IX domain were investigated using PMVEC cell lines that express ei- ther a full-length CA IX protein or a CA IX protein harboring a domain deletion. We found that the PG domain promotes intracel- lular pH homeostasis, migration, and network formation. The CA and IC domains mediate Akt activation but negatively regulate aerobic glycolysis. The IC domain also supports migration while inhibiting network formation. Finally, we show that exposure to acidosis suppresses aerobic glycolysis and migration, even though intracellular pH is maintained in PMVECs. Thus, we report that 1) the PG and IC domains mediate PMVEC migration and network formation, 2) the CA and IC domains support PI3K/Akt sig- naling, and 3) acidosis impairs PMVEC metabolism and migration independent of intracellular pH homeostasis.

First Page

L48

Last Page

L57

DOI

10.1152/ajplung.00337.2021

Publication Date

Summer 6-2022

Department

College of Medicine

Comments

Copyright © 2022 the American Physiological Society.

Please refer to publisher version for all inquires about this work at the following link: https://doi.org/10.1152/ajplung.00337.2021

Supplemental figures and videos, along with copyright and usage permission, can be found at the following publisher links:

Supplemental Fig. S1: https://doi.org/10.6084/m9.figshare.19847512.

Supplemental Fig. S2: https://doi.org/10.6084/m9.figshare.19857634.

Supplemental Videos S1–S6: https://doi.org/10.6084/m9.figshare.15138030.

Recommended Citation

Stevens, Reece P., et al. "Carbonic anhydrase IX proteoglycan-like and intracellular domains mediate pulmonary microvascular endothelial cell repair and angiogenesis." American Journal of Physiology-Lung Cellular and Molecular Physiology 323.1 (2022): L48-L57.