Browsing by Subject "Vascular biology"

Now showing 1 - 4 of 4
  • Thumbnail Image
    Item
    17β-Estradiol and estrogen receptor α protect right ventricular function in pulmonary hypertension via BMPR2 and apelin
    (American Society for Clinical Investigation, 2021-03-15) Frump, Andrea L.; Albrecht, Marjorie; Yakubov, Bakhtiyor; Breuils-Bonnet, Sandra; Nadeau, Valérie; Tremblay, Eve; Potus, Francois; Omura, Junichi; Cook, Todd; Fisher, Amanda; Rodriguez, Brooke; Brown, R. Dale; Stenmark, Kurt R.; Rubinstein, C. Dustin; Krentz, Kathy; Tabima, Diana M.; Li, Rongbo; Sun, Xin; Chesler, Naomi C.; Provencher, Steeve; Bonnet, Sebastien; Lahm, Tim; Medicine, School of Medicine
    Women with pulmonary arterial hypertension (PAH) exhibit better right ventricular (RV) function and survival than men; however, the underlying mechanisms are unknown. We hypothesized that 17β-estradiol (E2), through estrogen receptor α (ER-α), attenuates PAH-induced RV failure (RVF) by upregulating the procontractile and prosurvival peptide apelin via a BMPR2-dependent mechanism. We found that ER-α and apelin expression were decreased in RV homogenates from patients with RVF and from rats with maladaptive (but not adaptive) RV remodeling. RV cardiomyocyte apelin abundance increased in vivo or in vitro after treatment with E2 or ER-α agonist. Studies employing ER-α–null or ER-β–null mice, ER-α loss-of-function mutant rats, or siRNA demonstrated that ER-α is necessary for E2 to upregulate RV apelin. E2 and ER-α increased BMPR2 in pulmonary hypertension RVs and in isolated RV cardiomyocytes, associated with ER-α binding to the Bmpr2 promoter. BMPR2 is required for E2-mediated increases in apelin abundance, and both BMPR2 and apelin are necessary for E2 to exert RV-protective effects. E2 or ER-α agonist rescued monocrotaline pulmonary hypertension and restored RV apelin and BMPR2. We identified what we believe to be a novel cardioprotective E2/ER-α/BMPR2/apelin axis in the RV. Harnessing this axis may lead to novel RV-targeted therapies for PAH patients of either sex.
  • Thumbnail Image
    Item
    Frataxin deficiency promotes endothelial senescence in pulmonary hypertension
    (The American Society for Clinical Investigation, 2021-06-01) Culley, Miranda K.; Zhao, Jingsi; Tai, Yi Yin; Tang, Ying; Perk, Dror; Negi, Vinny; Yu, Qiujun; Woodcock, Chen-Shan C.; Handen, Adam; Speyer, Gil; Kim, Seungchan; Lai, Yen-Chun; Satoh, Taijyu; Watson, Annie M.M.; Al Aaraj, Yassmin; Sembrat, John; Rojas, Mauricio; Goncharov, Dmitry; Goncharova, Elena A.; Khan, Omar F.; Anderson, Daniel G.; Dahlman, James E.; Gurkar, Aditi U.; Lafyatis, Robert; Fayyaz, Ahmed U.; Redfield, Margaret M.; Gladwin, Mark T.; Rabinovitch, Marlene; Gu, Mingxia; Bertero, Thomas; Chan, Stephen Y.; Medicine, School of Medicine
    The dynamic regulation of endothelial pathophenotypes in pulmonary hypertension (PH) remains undefined. Cellular senescence is linked to PH with intracardiac shunts; however, its regulation across PH subtypes is unknown. Since endothelial deficiency of iron-sulfur (Fe-S) clusters is pathogenic in PH, we hypothesized that a Fe-S biogenesis protein, frataxin (FXN), controls endothelial senescence. An endothelial subpopulation in rodent and patient lungs across PH subtypes exhibited reduced FXN and elevated senescence. In vitro, hypoxic and inflammatory FXN deficiency abrogated activity of endothelial Fe-S–containing polymerases, promoting replication stress, DNA damage response, and senescence. This was also observed in stem cell–derived endothelial cells from Friedreich’s ataxia (FRDA), a genetic disease of FXN deficiency, ataxia, and cardiomyopathy, often with PH. In vivo, FXN deficiency–dependent senescence drove vessel inflammation, remodeling, and PH, whereas pharmacologic removal of senescent cells in Fxn-deficient rodents ameliorated PH. These data offer a model of endothelial biology in PH, where FXN deficiency generates a senescent endothelial subpopulation, promoting vascular inflammatory and proliferative signals in other cells to drive disease. These findings also establish an endothelial etiology for PH in FRDA and left heart disease and support therapeutic development of senolytic drugs, reversing effects of Fe-S deficiency across PH subtypes.
  • Thumbnail Image
    Item
    GPR68 Senses Flow and Is Essential for Vascular Physiology
    (Elsevier, 2018-04-19) Xu, Jie; Mathur, Jayanti; Vessières, Emilie; Hammack, Scott; Nonomura, Keiko; Favre, Julie; Grimaud, Linda; Petrus, Matt; Francisco, Allain; Li, Jingyuan; Lee, Van; Xiang, Fu-Li; Mainquist, James K.; Cahalan, Stuart M.; Orth, Anthony P.; Walker, John R.; Ma, Shang; Lukacs, Viktor; Bordone, Laura; Bandell, Michael; Laffitte, Bryan; Xu, Yan; Chien, Shu; Henrion, Daniel; Patapoutian, Ardem; Obstetrics and Gynecology, School of Medicine
    Mechanotransduction plays a crucial role in vascular biology. One example of this is the local regulation of vascular resistance via flow-mediated dilation (FMD). Impairment of this process is a hallmark of endothelial dysfunction and a precursor to a wide array of vascular diseases, such as hypertension and atherosclerosis. Yet the molecules responsible for sensing flow (shear stress) within endothelial cells remain largely unknown. We designed a 384-well screening system that applies shear stress on cultured cells. We identified a mechanosensitive cell line that exhibits shear stress-activated calcium transients, screened a focused RNAi library, and identified GPR68 as necessary and sufficient for shear stress responses. GPR68 is expressed in endothelial cells of small-diameter (resistance) arteries. Importantly, Gpr68-deficient mice display markedly impaired acute FMD and chronic flow-mediated outward remodeling in mesenteric arterioles. Therefore, GPR68 is an essential flow sensor in arteriolar endothelium and is a critical signaling component in cardiovascular pathophysiology.
  • Thumbnail Image
    Item
    Origin, prospective identification, and function of circulating endothelial colony-forming cells in mice and humans
    (The American Society for Clinical Investigation, 2023-03-08) Lin, Yang; Banno, Kimihiko; Gil, Chang-Hyun; Myslinski, Jered; Hato, Takashi; Shelley, William C.; Gao, Hongyu; Xuei, Xiaoling; Basile, David P.; Yoshimoto, Momoko; Prasain, Nutan; Tarnawsky, Stefan P.; Adams, Ralf H.; Naruse, Katsuhiko; Yoshida, Junko; Murphy, Michael P.; Horie, Kyoji; Yoder, Mervin C.; Pediatrics, School of Medicine
    Most circulating endothelial cells are apoptotic, but rare circulating endothelial colony-forming cells (C-ECFCs), also known as blood outgrowth endothelial cells, with proliferative and vasculogenic activity can be cultured; however, the origin and naive function of these C-ECFCs remains obscure. Herein, detailed lineage tracing revealed murine C-ECFCs emerged in the early postnatal period, displayed high vasculogenic potential with enriched frequency of clonal proliferative cells compared with tissue-resident ECFCs, and were not committed to or derived from the BM hematopoietic system but from tissue-resident ECFCs. In humans, C-ECFCs were present in the CD34bright cord blood mononuclear subset, possessed proliferative potential and in vivo vasculogenic function in a naive or cultured state, and displayed a single cell transcriptome sharing some umbilical venous endothelial cell features, such as a higher protein C receptor and extracellular matrix gene expression. This study provides an advance for the field by identifying the origin, naive function, and antigens to prospectively isolate C-ECFCs for translational studies.