We have the pleasure of bringing together for the readers of Frontiers in Cardiovascular
Medicine, three groups of investigators to discuss their interests in the topic of
endothelial cell—cardiomyocyte crosstalk in cardiac remodeling. Notably, the three
manuscripts offer differing perspectives on the topic, attesting to its complex and
dynamic nature. What is clear from the series is the rich interaction between cardiomyocytes
and endothelial cells of the heart, reflecting the close physical proximity between
the two cell types that is important for normal heart function and health.
Gogiraju et al. provide a comprehensive accounting of the important signaling molecules
of both endothelial cells and cardiomyocytes that regulate angiogenesis. These include
various growth factors, such as vascular endothelial growth factor (VEGF), placental
growth factor (PGF), platelet-derived growth factors (PDGFs), basic fibroblast growth
factor (bFGF), epidermal growth factors (EGFs), and hepatocyte growth factor (HGF).
This contribution also provides an overview of endothelial transcription factors that
regulate angiogenic growth factor expression, as well as a discussion of possible
mechanisms for the reduction in angiogenesis with pathological cardiac hypertrophy.
These include an imbalance of pro- and anti-angiogenic growth factors, endothelial
phosphatases as mediators of angiogenic resistance, endothelial cell death, and epigenetic
control of angiogenic gene transcription.
Zeng and Chen focus their contribution on the NAD-dependent deacetylase, sirtuin-3
(SIRT3), which is normally found in mitochondria. These investigators recently reported
the novel observation that SIRT3-deficient endothelial cells exhibit decreased basal
glycolysis and glycolytic capacity (1), which is associated with increased mitochondrial
ROS formation. Notably, in endothelial cells glycolysis and not oxidative phosphorylation
is preferentially used to generate ATP to maintain normal cellular functions, including
angiogenesis. The review by Zeng and Chen discusses evidence to support the provocative
suggestion that impairment of SIRT3-mediated endothelial cell metabolism and angiogenesis
may promote cardiomyocyte hypoxia and myocardial fibrosis, leading to diastolic dysfunction
and heart failure with preserved ejection fraction (HFpEF). Unresolved is the issue
of whether endothelial SIRT3 deficiency or its compromised activity occurs in HFpEF
patients, and whether this progresses over time to systolic dysfunction, which is
also associated with microvascular rarefaction (2). Also, it would be interesting
to investigate whether there is a link between endothelial SIRT3 deficiency and the
increased activity of inducible nitric oxide synthase (iNOS) that was recently implicated
in the pathogenesis of HFpEF (3).
Zouein et al. provide a brief overview of the importance that the transcription factor
STAT3 has been shown to play in the dialog between endothelial cells and cardiomyocytes.
This occurs under both normal and diseased states, such as peripartum cardiomyopathy,
and involves both genomic and non-genomic actions of this versatile transcription
factor. Part of the role of STAT3 in endothelial cell—cardiomyocyte crosstalk involves
miRNAs, not only within each cell type, but within endosomal vesicles that are taken
up by cardiomyocytes and affect their gene expression profile. These authors also
present the novel idea that the non-genomic actions of STAT3 in endothelial cells
and cardiomyocytes may serve as a sensor in the heart that fine tunes its response
to stress. This sentinel role would involve its translocation to mitochondria, endoplasmic
reticulum, and nucleus, as well as its presence at intercalated disc (in the case
of cardiomyocytes). The importance of the non-genomic actions of STAT3 in vivo, particularly
with regard to direct actions in mitochondria, is still controversial (4); although
the role of STAT3 in directly regulating mitochondrial function in cardiac myocytes
has been questioned on stoichiometric grounds (5), such a role in endothelial cells
may be less problematic, since these cells have a lower number of mitochondria. Not
specifically addressed in this article is the possibility that nuclear accumulation
of unphosphorylated STAT3 (U-STAT3), due to the release of IL-6 from endothelial cells,
may act to sustain pressure overload-induced cardiac hypertrophy (6, 7).
Although endothelial cell—cardiomyocyte crosstalk has been extensively investigated,
there is more that needs to be explored and understood. Lacking, is an integrated
scheme for the crosstalk under physiological and pathological conditions that is based
on a systems biology approach. That approach needs to incorporate aspects of the immune
system. It needs as well to take into consideration the contribution of metabolism,
oxidative stress, neuronal signaling, and other factors in coordinating the dialog.
Many questions remain to be answered, but the experimental methods have lagged behind
and newer technologies are sorely needed. Hopefully, the ensuing decade will see the
development of new experimental approaches and a renaissance in studies investigating
this important topic.
Author Contributions
All authors listed have made a substantial, direct and intellectual contribution to
the work, and approved it for publication.
Conflict of Interest Statement
The authors declare that the research was conducted in the absence of any commercial
or financial relationships that could be construed as a potential conflict of interest.