Abstract
Adrenaline and noradrenaline are produced within the heart from neuronal and non-neuronal sources. These adrenergic hormones have profound effects on cardiovascular development and function, yet relatively little information is available about the specific tissue distribution of adrenergic cells within the adult heart. The purpose of the present study was to define the anatomical localization of cells derived from an adrenergic lineage within the adult heart. To accomplish this, we performed genetic fate-mapping experiments where mice with the cre-recombinase (Cre) gene inserted into the phenylethanolamine-n-methyltransferase (Pnmt) locus were cross-mated with homozygous Rosa26 reporter (R26R) mice. Because Pnmt serves as a marker gene for adrenergic cells, offspring from these matings express the β-galactosidase (βGAL) reporter gene in cells of an adrenergic lineage. βGAL expression was found throughout the adult mouse heart, but was predominantly (89%) located in the left atrium (LA) and ventricle (LV) (p<0.001 compared to RA and RV), where many of these cells appeared to have cardiomyocyte-like morphological and structural characteristics. The staining pattern in the LA was diffuse, but the LV free wall displayed intermittent non-random staining that extended from the apex to the base of the heart, including heavy staining of the anterior papillary muscle along its perimeter. Three-dimensional computer-aided reconstruction of XGAL+ staining revealed distribution throughout the LA and LV, with specific finger-like projections apparent near the mid and apical regions of the LV free wall. These data indicate that adrenergic-derived cells display distinctive left-sided distribution patterns in the adult mouse heart.
Highlights
Cardiac development is a multifarious process that involves cell specification, determination, patterning, migration, and growth
Cells that express bgal are indicative of cells that are derived from an adrenergic lineage due to their expression of Cre-recombinase from the phenylethanolamine n-methyltransferase (Pnmt) genetic locus. bgal expression is readily visualized as blue cells following XGAL histological staining
Some of the most strongly positive XGAL staining was consistently observed in the left atrium (LA); thereby indicating that many of the myocytes in the LA were derived from an adrenergic lineage
Summary
Cardiac development is a multifarious process that involves cell specification, determination, patterning, migration, and growth. This is achieved through precise regulation of gene expression within several cell types during embryonic development. Adrenergic cells are distributed throughout the developing heart, including regions associated with pacemaking and conduction tissue [2,3]. Cardiac adrenergic cells appear as early as embryonic day 8.5 (E8.5) [4]. These cells are responsible for the production and secretion of adrenaline and noradrenaline [2,3,5]. Immunohistochemical staining experiments for adrenergic biosynthetic enzymes, including tyrosine hydroxylase (Th), dopamine b-hydroxylase (Dbh), and phenylethanolamine n-methyltransferase (Pnmt), indicated transient expression of an adrenergic cellular phenotype in different regions of the heart as development proceeds [3,6]
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