Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 116, Issue 27, Pages 13414-13423Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1903510116
Keywords
sympathetic neurons; cardiac innervation; tyrosine hydroxylase; hypoxia; coronary artery branching
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Funding
- Czech Science Foundation [17-04719S, 19-07378S]
- Czech Academy of Sciences [RVO 86652036]
- European Regional Development Fund [BIOCEV CZ. 1.05/1.1.00/02.0109]
- Czech Ministry of Education, Youth and Sports [Progres Q29, Progres Q38]
- European Cooperation in Science and Technology (INTER-COST) Award [LTC17023]
- Czech Bio-Imaging Award [LM2015062]
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The molecular mechanisms regulating sympathetic innervation of the heart during embryogenesis and its importance for cardiac development and function remain to be fully elucidated. We generated mice in which conditional knockout (CKO) of the Hif1a gene encoding the transcription factor hypoxia-inducible factor 1 alpha (HIF-1 alpha) is mediated by an Islet1-Cre transgene expressed in the cardiac outflow tract, right ventricle and atrium, pharyngeal mesoderm, peripheral neurons, and hindlimbs. These Hif1aCKO mice demonstrate significantly decreased perinatal survival and impaired left ventricular function. The absence of HIF-1 alpha impaired the survival and proliferation of preganglionic and postganglionic neurons of the sympathetic system, respectively. These defects resulted in hypoplasia of the sympathetic ganglion chain and decreased sympathetic innervation of the Hif1aCKO heart, which was associated with decreased cardiac contractility. The number of chromaffin cells in the adrenal medulla was also decreased, indicating a broad dependence on HIF-1 alpha for development of the sympathetic nervous system.
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