Science - USA (2020-08-21)

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chronic inflammation and to en-
sure tissue repair. Thus, a pre-
cise understanding of the exact
molecular mechanisms governing
vascular regression in retinal and
other diseases is of the utmost
clinical importance.
Using high-resolution droplet-
based RNA sequencing and sophis-
ticated bioinformatics approaches
in animal models of retinopathy,
Binet et al. were able to effectively
tease out the main players of vas-
cular regression at the molecular,
cellular, and tissue levels. They
showed in mice and humans that
the entire process relies on the
innate immune system, namely
neutrophils, which are deployed
during the late phase of retinal
disease, which is associated with
vascular regression rather than
vascular growth.
Neutrophils serve as a first line
of innate immunity against patho-
gens by means of oxidative burst,
phagocytosis, and release of web-
like DNA and protein structures
called NETs. Besides their origi-
nally defined role in pathogen de-
fense ( 5 ), NETs also mediate severe
inflammatory reactions of primar-
ily a destructive nature, such as
cancer metastasis and tissue and
organ damage within the vascu-
lar, pulmonary, and renal systems
( 6 ). Most recently, NETs have been
implicated in organ damage and
other complications of coronavi-
rus disease 2019 (COVID-19) ( 7 ).
Binet et al. show that during the
process of retinal vascular repair,
NETs perform a very different
function of marking senescent vas-
cular branches for pruning (see the figure).
Under different circumstances, this tag-
ging for destruction might lead to impaired
blood supply and eventually to organ fail-
ure; however, in ischemic retinopathy, this
process serves an essential prerequisite for
tissue repair. It remains to be determined
whether this role of NETs is restricted only
to tissues of primarily postmitotic nature,
such as the retina and central nervous sys-
tem, or whether it also operates in other
pathologies, such as neoplasms, or even
whether it might underlie developmental
vascular restructuring.
Involvement of NETs in other patholo-
gies seems to be likely because NETosis is
stimulated by a specific combination of fac-
tors, including interleukin-1b (IL-1b) and
C-X-C motif chemokine 1 (CXCL1), which
are secreted by senescent cells and found

not only in aging but also during develop-

ment ( 8 ) and in actively growing tissues

such as tumors ( 9 ). In diseased retinas, this

senescence-associated secretory phenotype

(SASP) is observed in endothelial cells, peri-

cytes, astrocytes, and Müller glia but not in

retinal ganglion cells (which connect pho-

tosensitive cells in the retina to the optic

nerve), which are also known to undergo se-

nescence. Together, these findings indicate

that various types of senescent cells might

be able to attract neutrophils and deploy

NETs. It will be interesting to explore why

only certain types of senescent cells pro-

mote NETs.

Acquisition of a SASP signature is be-

lieved to be mainly detrimental because

of its contribution to inflammation, oxida-

tive stress, thrombosis (blood clotting), and

metabolic imbalance ( 10 ). In endothelium,

the SASP signature includes pro-

angiogenic factors that promote

vascularization in tumors ( 9 ) and

in age-related diseases, including

retinopathy ( 11 ). In tumors, SASP

facilitates drug delivery, thus mak-

ing tumors vulnerable to chemo-

therapy ( 9 ). In proliferative dia-

betic retinopathy, however, SASP

cytokines such as IL-6, IL-8, and

VEGF directly promote pathologi-

cal vascular growth, delaying tis-

sue repair ( 11 ). However, similar to

Binet et al., studies found benefi-

cial roles of SASP in tissue growth

( 8 ) and wound healing ( 12 ) as in-

ducers of stem-like characteristics

of keratinocytes, driving epithelial

regeneration ( 13 ).

It is notable that the retinal

vasculature activates a “self-cor-

recting” program by acquiring the

SASP. Binet et al. demonstrate that

the SASP signature is associated

with activation of RAS pathways

within a population of senescent

retinal endothelial cells. In cancer,

proangiogenic SASP components

are the result of inhibition rather

than activation of the KRAS path-

way ( 9 ). Nevertheless, even in can-

cer, SASP promotes therapeutically

beneficial vascular remodeling.

Together, these results support the

concept that cellular senescence

has substantial value as a therapeu-

tic target in a variety of disorders

associated with vascular dysfunc-

tion, and that induction of vascu-

lar senescence is a prerequisite for

vascular remodeling and optimi-

zation. Moreover, because most of

the vasculature requires active and

uninterrupted maintenance, this

senescence-induced regression and remod-

eling aided by neutrophils might also be ap-

plicable to vascular homeostasis. j

REFERENCE AND NOTES

1. A. R. Pries, T. W. Secomb, Physiol. 29 , 446 (2014).


2. E. C. Watson, Z. L. Grant, L. Coultas, Cell. Mol. Life Sci. 74 ,
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3. C. Korn, H. G. Augustin, Dev. Cell 34 , 5 (2015).


4. F. Binet et al., Science 369 , eaay5356 (2020).


5. V. Brinkmann et al., Science 303 , 1532 (2004).


6. V. Papayannopoulos, Nat. Rev. Immunol. 18 , 134 (2018).


7. B. J. Barnes et al., J. Exp. Med. 217 , e20200652 (2020).


8. D. Muñoz-Espín et al., Cell 155 , 1104 (2013).


9. M. Ruscetti et al., Cell 181 , 424 (2020).


10. J. Sabbatinelli et al., Front. Physiol. 10 , 1523 (2019).


11. M. Oubaha et al., Sci. Transl. Med. 8 , 362ra144 (2016).


12. M. Demaria et al., Dev. Cell 31 , 722 (2014).


13. B. Ritschka et al., Genes Dev. 31 , 172 (2017).

ACKNOWLEDGMENTS

The authors are supported by National Institutes of Health

(HL142772 and HL145536).

10.1126/science. abd7063

Neutrophil

NETosis

Senescent

vasculature

NETS

Endothelial apoptosis

Vascular normalization

Tissue repair

SASP

INSIGHTS | PERSPECTIVES

Vascular senescence facilitates tissue repair

Dysfunctional senescent retinal vasculature produces senescence-

associated secretory phenotype (SASP) components, attracts

neutrophils, and stimulates the extrusion of neutrophil extracellular

traps (NETosis, see photo below). This causes endothelial cell

apoptosis and vascular pruning, which is essential for vascular repair

and tissue recovery in ischemic retinopathy.

920 21 AUGUST 2020 • VOL 369 ISSUE 6506

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