TEM 1313 No.
of Pages 2
Spotlight
The Endothelial–
Metabolic Axis: A
Novel Cardiometabolic
Disease Target
Jason C. Kovacic1,*
Endothelial to mesenchymal tran-
sition (EndMT) involves cellular
phenotypic switching from an
endothelial to mesenchymal state.
Interest in EndMT has been
increasing with the appreciation
that it has an important role in sev-
eral cardiovascular diseases. New
evidence indicates that fatty acid
oxidation (FAO) and cell metabo-
lism are major factors controlling 84_TD$IF]W
[ hile EMT has been widely explored and
this process. is known to be of importance in develop-
The scientific field of cellular transition is
expanding at a very fast pace. As a com-
ment that I revisit later, the recent paper
and the focus of this Spotlight article, ‘A
Metabolic Basis for Endothelial to Mesen-
chymal Transition’ by Xiong et al. [1], is yet
another major addition to the literature
and body of knowledge regarding this
process. With their article, Xiong et al.
[1] have made a significant contribution
and effectively opened an entirely new
area of research, namely that the process
of EndMT is regulated by FAO. Moreover,
FAO and metabolic factors appear to be
intimately involved with EndMT at multiple
levels and, conversely, cells undergoing
EndMT exhibit an altered metabolic sta-
tus. But more of this later. First, how did
we get to this point of a veritable explo-
sion of interest in cell transition; what is it,
and why all the fuss?
Interest in cell transition began over five
decades ago with pioneering research
showing that epithelial cells in the devel-
oping chick can transition in phenotype
to become embryonic mesoderm [2,3].
After some debate, the process was ulti-
mately named [83_TD$IF]epithelial to mesenchymal
diseases, it is unsurprising that intense
efforts have recently been invested to
transition (EMT). In brief, EMT involves a unravel and understand EndMT. Until
phenotypic switch from regularly
arranged epithelial cells that are aligned
now, common wisdom was that it was
primarily under the control of the TGF-b
along a basement membrane with clas- pathway, which includes the rich panoply
sic features of apicobasal cell polarity of up- and downstream members of the
TGF-b signaling cascade (Figure 1).
and abundant expression of intercellular
adhesion molecules, to mesenchymal Beyond the TGF-b superfamily, other
cells that exhibit features such as loss reported mediators of EndMT included
of cell polarity and cell–cell adhesion, certain interleukins and FGFs, Wnt/b-cat-
increased migratory capacity, and enin signaling, and oxidative stress. How-
increased mesenchymal protein and ever, it is widely agreed that much
gene expression [4]. Classic mesenchy- remains to be discovered and understood
mal cell types include mesodermal cells, about EndMT. It is in this context that the
fibroblasts, smooth muscle cells, osteo- paper ‘A Metabolic Basis for Endothelial
cytes, chondrocytes, and adipocytes to Mesenchymal Transition’ was pub-
(Figure 1). lished from the laboratory of Toren Finkel
[1].
In this study, the authors undertook a
thorough exploration of the role of cellular
ment, malignancy, and adult tissue fibro-
metabolism in EndMT [1]. As a starting
sis, studies of EndMT have been slower to
point, they leveraged standard in vitro
emerge. Given that the endothelium is a
EndMT models based on TGF-b + inter-
subtype of epithelium, EndMT can be
leukin-1b stimulation, and immediately
considered as a subtype of EMT. While
identified that EndMT is associated with
reports from the mid-1970s suggested a
an increase in certain short-chain acylcar-
role for EndMT during cardiovascular
nitines, reduced endothelial FAO, and an
development [5], it was only as recently
early decrease in carnitine palmitoyltrans-
as 2007 that the first report emerged that
ferase 1A (CPT1A) levels, an enzyme that
implicated EndMT in adult cardiovascular
has an obligate role in FAO. Accordingly,
disease; in this case that endothelial cells
overexpression of CPT1A effectively
can undergo EndMT and participate in
blocked the induction of EndMT, while
cardiac fibrosis [6]. Since then, interest
CPT1A knockdown induced EndMT in
in EndMT has grown exponentially. For
vitro in the absence of TGF-b or interleu-
example, among many studies, endothe-
kin-1b. Although CPT2 levels were
lial cells were recently shown to transition
unchanged with EndMT, knockdown of
to fibroblast-like cells and migrate into
CPT2 induced EndMT in a similar fashion
atherosclerotic plaques, where they are
to CPT1A knockdown. To further dissect
associated with the degree of plaque
these pathways, Xiong et al. [1] then dem-
instability and rupture [7]. Other adult car-
onstrated that EndMT was also associ-
diovascular diseases and/or states where
ated with a reduction in acetyl-CoA levels,
a role for EndMT has now been sug-
and that an increase in cytosolic acetyl-
gested include pulmonary hypertension,
CoA suppressed TGF-b-induced EndMT,
vein graft remodeling, and cardiac valve
while a reduction in cytosolic acetyl-CoA
pathology [4].
levels activated EndMT. In addition, ace-
tyl-CoA was found to regulate EndMT by
Given this seemingly pervasive presence altering SMAD7 protein levels. In vivo,
across a spectrum of adult cardiovascular using transgenic mice with endothelial-
Trends in Endocrinology & Metabolism, Month Year, Vol. xx, No. yy 1
 TEM 1313 No. of Pages 2

In conclusion, we appear to be glimpsing

just the proverbial ‘tip of the iceberg’ in
terms of the seemingly profound and bidi-
A metabolic basis for EndMT: rectional inter-relations between the
Previously known major EndMT regulators:
- EndMT is associated with reduced FAO endothelium and metabolism at both
- FAO modulates EndMT - TGF-β superfamily, including SMADs,
BMP, ZEB1/2, and associated the local and systemic levels. With the
- CPT1A is reduced with EndMT
- CPT2 knockdown promotes EndMT miRNAs and IncRNAs endothelium being arguably one of the
- FGF family
- ModulaƟon of FAO and cell largest organs in the body, and with the
metabolism is a novel target for - Wnt/β-catenin signaling
current global epidemic of obesity and
several cardiovascular diseases - OxidaƟve stress
related cardiometabolic diseases, the
endothelial–metabolic axis promises to
be a hot area of research for the coming
years.

Acknowledgments
J.K. acknowledges research support from the
National Institutes of Health (R01HL130423), Fonda-
tion Leducq (Transatlantic Networks of Excellence
Award), and the American Heart Association
(14SFRN20490315; 14SFRN20840000).
Figure 1. Endothelial to Mesenchymal Transition (EndMT) and Its Key Signaling Pathways. At the
top is shown typical endothelial cells with underlying basement membrane. With EndMT, endothelial cells 1
The Zena and Michael A. Wiener Cardiovascular Institute
undergo a series of fundamental phenotypic changes and acquire a mesenchymal cell phenotype (bottom). and Cardiovascular Research Center, Icahn School of
Produced using Servier medical art. Abbreviations: CPT1A, carnitine palmitoyltransferase 1A; FAO, fatty acid Medicine at Mount Sinai, New York, NY, USA
oxidation; lncRNA, long noncoding RNA.
*Correspondence:
jason.kovacic@mountsinai.org (J.C. Kovacic).
the endothelium (e.g., obesity is associ-
specific knockout of CPT2, Xiong et al. [1]
https://doi.org/10.1016/j.tem.2018.03.015
ated with endothelial dysfunction [8]),
were able to validate many of their in vitro
findings. Notably, they were able to show begs one final question: does this control References
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