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HERBERT ZIMMERMANN Y COLS. AN. R. ACAD. NAC. FARM.

to hydrolyze ATP to AMP and ADP to AMP it blocks platelet
aggregation in response to ADP thus supporting blood flow.
Accordingly, NTPDase1 knockout mice reveal increased infarct
volumes. Infusion of soluble derivatives of NTPDase1 or soluble plant
apyrases improves blood flow and tissue reperfusion following
ischemia and in tissue transplants (41, 84). NTPDase2 produces ADP
from ATP and thus promotes platelet activation. The enzyme is
located at adventitial surfaces of the muscularized vessels,
microvascular pericytes of some tissues and organs as the heart
and the stromal cells and would potentially favor ADP-induced
platelet aggregation at sites of vessel injury and thus support
hemostasis (85, 86).

In another setting, portal fibroblasts were suggested to regulate
bile duct epithelial proliferation via expression of NTPDase2.
NTPDase2 inhibits and knockdown of NTPDase2 by RNA
interference increases the proliferation of epithelial cells, apparently
by compromising their nucleotide scavenging effect. Loss of portal
fibroblast NTPDase2 following bile duct ligation may thus mediate
the bile ductular proliferation typical of obstructive choleostasis (87).

BROAD FUNCTIONAL IMPACT OF ECTO-NUCLEOTIDASES

As shown by a considerable number of immunocytochemical or
enzyme histochemical studies defined ecto-nucleotidases are
expressed in specific tissues or cellular systems. In many cases a
resolution at the electron microscopic level would be desirable to
identify their exact localization and site of action. This particularly
applies to the nervous system. Yet, the demonstration of the
expression of an enzyme in a defined cellular setting does not permit
an immediate anticipation of its functional impact. This depends on
the actual catalytic activity and the scenario of the surrounding
purinergic receptors. But the identification of ecto-nucleotidases may
serve as a first indicator of a functional involvement of nucleotide
signaling pathways. Presently, the best tool for studying the
functional impact of a particular ecto-nucleotidase in a defined
purinergic signaling pathway is the use of specific high affinity
inhibitors (if available), the knockdown by RNA interference or the

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