S C I E N C E ’ S C O M PA S S

65 materials of different activities. Knowl- The analysis, simulation, and control to understand structure formation in bio-
64 edge of reaction mechanisms including of complex nonlinear processes benefit logical systems with gradients in electri-
63 self-organization processes on catalytic many areas of science and engineering. cal potential.
62 surfaces can be exploited through join- For example, interest in the dynamics of A rich harvest of basic knowledge will
61 ing sets of microreactors coupled by dif- electrochemical systems has been re- continue to result from studies of the self-
60 fusive transport of adsorbed molecules. vived because of progress in the analysis organization of surface reactions, as exem-
59 Moreover, the role of promoters, a cen- and simulation of spatiotemporal pat- plified by the report by Sachs et al. (1). I
58 tral topic in catalysis, is now accessible terns, such as the inhomogeneous distri- expect to see practical applications within
57 to detailed investigations. bution of reaction currents (9). Spa- the first decade of the 21st century in many
56 The study of model catalytic and elec- tiotemporal patterns form on electrode areas, including electrocatalysis in fuel
55 trochemical systems also contributes to surfaces during electrochemical reactions cells, corrosion control, electrochemical
54 the general understanding of nonlinear because of a subtle interplay between machining of metals, and—most important-
53 dynamics. Major issues are the control of electrode kinetics, the conductivity and ly—industrial and environmental catalysis.
52 spatiotemporal chaos and the study and composition of the electrolyte, the geom-
51 the control of the catalytic and electro- etry of the electrochemical cell, and the References
50 chemical reaction dynamics. The suppres- external electric circuit. The nature of the 1. C. Sachs, M. Hildebrand, S. Völkening, J. Wintterlin, G.
Ertl, Science 293, 1635 (2001).
49 sion of chemical turbulence in the catalyt- patterns is determined by long-range 2. P. S. Cremer et al., J. Phys. Chem. 100, 16302 (1996).
48 ic oxidation of carbon monoxide on a coupling between reacting sites through 3. G. A. Somorjai, G. Rupprechter, J. Phys. Chem. B 103,
47 platinum single-crystal surface by global the electric field. This coupling can be 1623 (1999).
4. T. Dellwig et al., Phys. Rev. Lett. 85, 776 (2000).
46 delayed feedback via the carbon monox- easily fine tuned, opening a whole new 5. G. Sankar, J. M. Thomas, Top. Catal. 8, 1 (1999).

Downloaded from www.sciencemag.org on March 19, 2015

45 ide partial pressure is an impressive ex- window toward the understanding of pat- 6. E. Schütz et al., Catal. Lett. 54, 181 (1998).
44 ample (7). Another is the synchronization tern formation. Recently, the adjustment 7. M. Kim et al., Science 292, 1357 (2001).
8. W. Wang, I. Z. Kiss, J. L. Hudson, Chaos 10, 248
43 and cluster formation in large sets of of long-range inhibition by migration (2000).
42 chaotic electrochemical oscillators con- currents has led to the appearance of 9. K. Krischer, in Modern Aspects of Electrochemistry,
41 sisting of nickel electrodes in sulfuric structures on the surface of an electrode vol. 32, B. E. Conway, J. O. M. Bockris, R. E. White, Eds.
(Kluwer Academic/Plenum, New York, 1999), pp.
40 acid via global coupling through external that could be identif ied as Turing pat- 1–142.
39 resistors (8). terns (10). Such findings may even help 10. Y.-J. Li et al., Science 291, 2395 (2001).
38
37 PERSPECTIVES: BIOMEDICINE
36 surprisingly, therefore, the absence of
35
34 Clotting Factors Build any of these clotting factors (TF, FVIIa,
FVa, FXa, prothrombin, fibrinogen) pre-
33 disposes animals to severe, often life-
32
31
Blood Vessels threatening, bleeding disorders (4, 5).
Thrombin further enhances blood clot
30 Peter Carmeliet for mation by activating circulating
29 platelets, which then aggregate (see the
28 figure). This clotting enzyme promotes
27 or blood vessels to deliver oxygen to PAR1 (2). These findings emphasize the activation of human platelets by cleaving
26
25
24
F distant tissues, they must remain in-
tact. When the vessel is injured,
bleeding is stopped by clotting (coagula-
importance of thrombin and its receptors
in angiogenesis, not only in the embryo
but also in the adult, where angiogenesis
the amino-terminal extracellular domain
of PAR1 or PAR4, cleavage of either be-
ing sufficient to trigger platelet aggrega-
23 tion) factors that form a thrombus (clot) has been implicated in numerous disor- tion (1, 6). PAR3 and PAR4 are ex-
22 of fibrin threads that trap platelet aggre- ders including cancer and ischemic heart pressed by mouse platelets but, curiously,
21 gates. The protease thrombin is essential disease (3). PAR3 is an accessory cofactor for PAR4
20 for fibrin formation and platelet activa- The primary task of the clotting sys- activation at low thrombin concentrations
19 tion. Platelets become activated when tem is to form blood clots composed of (7). In contrast to the residual thrombin
18 thrombin binds to several protease-acti- fibrin and platelet aggregates. Tissue fac- response in PAR3-def icient platelets,
17 vated G protein-coupled receptors (PARs) tor, the initiator of blood coagulation, PAR4-deficient platelets lose all throm-
16 expressed on their surface (1). One mem- usually remains separate from blood and bin signaling, and PAR4-deficient mice,
15 ber of the PAR family, PAR1, is not ex- circulating clotting factors. It is ex- although viable, suffer prolonged bleed-
14 pressed by mouse platelets—yet, mouse pressed by smooth muscle cells in and ing. Remarkably, however, despite severe
13 embryos lacking this receptor die of fatal surrounding blood vessels, and at low platelet defects, PAR4-deficient embryos
12 bleeding. The question is why? Emerging levels by blood cells or activated en- develop nor mally, indicating that
11 evidence implicates the clotting system in dothelial cells that line blood vessels. At platelets are not essential for blood clot-
10 the building and stabilization of new sites of vascular injury, plasma coagula- ting (hemostasis) in the embryo. More-
9 blood vessels (angiogenesis) during em- tion factor VIIa (FVIIa) contacts ex- over, genetic studies suggest that fibrino-
8 bryonic development. On page 1666 of travascular tissue factor, thereby trigger- gen is also not required for embryonic
7 this issue, Griffin et al. report that ex- ing the coagulation cascade (see the fig- hemostasis. As expected, loss of PAR2,
6 pression of PAR1 by endothelial cells res- ure). Tissue factor is a cofactor for acti- which is not expressed by platelets, does
5 cues the fatal vessel fragility and bleeding vation of factor X (FX) by FVIIa. Acti- not affect hemostasis (6). Surprisingly, as
4 of mouse embryos engineered to lack vated factor X (FXa) with the assistance Griffin et al. report, loss of PAR1 (which
3 of cofactor Va (FVa) then converts pro- is not expressed by mouse platelets)
2 The author is at the University Leuven, Herestraat thrombin to active thrombin, which con- leads to fatal bleeding defects in a frac-
1 49, Leuven, B-3000, Belgium. verts circulating fibrinogen to fibrin. Not tion of early mouse embryos (2). Yet,

1602 31 AUGUST 2001 VOL 293 SCIENCE www.sciencemag.org


65 PAR1-deficient platelets aggregate nor-
64 mally in response to thrombin.
63 Why then do 50% of PAR1-deficient
62 mouse embryos die of bleeding? As Grif-
61 fin et al. demonstrate, the answer may lie
60 in the involvement of coagulation factors
59 in the building and stabilization of new
58 blood vessels (see the figure). When blood
57 vessels grow, they initially consist only of
56 fragile endothelial cells. Stabilization of
55 these naked endothelial vessels depends
54 on the recruitment of smooth muscle pre-
53 cursor cells, which, upon differentiation,
52 produce an extracellular matrix that
51 strengthens and matures newly forming
50 vessels. Vascular endothelial growth factor
49 (VEGF) initiates endothelial growth,
48 whereas platelet-derived growth factor
47 (PDGF) and angiopoietin are essential for
46 vessel wall stabilization (3).
45 Activation of angiogenic signaling
44 pathways is an integral part of the cellular
43 initiation of coagulation. Although nor-
42 mally absent from quiescent endothelium,
41 tissue factor is expressed in angiogenic
40 endothelium (for example, in tumor ves-
39 sels). Tissue factor and FVIIa could stim-
38 ulate angiogenesis by down-regulating the
37 angiogenic inhibitor thrombospondin-1
36 and by up-regulating expression of VEGF,
35
fibroblast growth factor–5 (FGF-5), pro-
34 teinases (collagenases) and their receptors
33 (u-PAR), as well as a number of other tar-
32 gets (8). Tissue factor is expressed consti-
31 tutively in smooth muscle cells and to-
30 gether with FVIIa could—by amplifying
29 the activity of PDGF—also assist in re-
28 cruiting smooth muscle cells during ves-
27 sel stabilization. FXa, a downstream prod-
26 uct of the tissue factor/FVIIa pathway, al-
25 so stimulates growth of smooth muscle
24 cells. Apart from generating a provisional
23 fibrin scaffold that attracts migrating vas-
22 cular cells, thrombin could stimulate an-
21 giogenesis by activating PAR1, PAR2, and
20 possibly PAR3 on endothelial cells.
19 Thrombin increases the expression of
18 VEGF receptors and nitric oxide (a down-
17 stream mediator of VEGF) by endothelial
16 cells, promotes production and extravasa-
15 tion of matrix proteins, loosens endothe-
14 lial cells from the extracellular matrix by
13 up-regulating and activating metallopro-
12 teinases, and induces endothelial cell pro-
11 liferation and migration (1, 6). Thrombin
10 may also recruit smooth muscle cells by
9 up-regulating endothelial expression of
8 PDGF (1, 6). Once the naked endothelial
7 vessels are covered, thrombin, by activat-
6 ing PAR1, PAR3, and PAR4, could stimu-
5 late smooth muscle cell differentiation
4 and growth and regulate vessel tone. By
3 activating the hypoxia-inducible transcrip-
2 tion factor HIF-1α, thrombin triggers ex-
1 pression of a master transcription factor,
www.sciencemag.org
S C I E N C E ’ S C O M PA S S
which up-regulates production of numer- cell–derived tryptase outside the vessel
ous angiogenic molecules (3, 9). In the wall, is likely to be activated by FVIIa in
adult, thrombin can further amplify angio- the vessel wall. However, activation in the
genesis by releasing VEGF, angiopoietin- vessel wall only happens when sufficient
1, and other angiogenic molecules from tissue factor and FXa are present—as is
platelets. Thus, when coagulation is initi- precisely the case for angiogenic endothe-
ated, a cascade of angiogenic signals is al- lial cells (12). The tissue factor/FVIIa/FXa
so generated. Together, coagulation and complex also efficiently activates PAR1
angiogenesis could cooperate in stabiliz- (12). Thus, even though thrombin is likely
ing new blood vessels, repairing injured to be the primary activator of PAR1, up-
vessels, and stimulating the sprouting of stream coagulation factors may also acti-
new vessels (see the figure). vate this thrombin receptor. Cross talk be-
A Prothrombin
Thrombin Hemostasis
FVIIa FVIIa FXa via fibrin formation
TF TF
PAR-2 PAR-1 PAR-3 PAR-4
Angiogenesis Angiogenesis Hemostasis
via release of VEGF via signaling through via platelet
and proteinases VEGF, PDGF, and HIF-1 aggregation
Stabilization of fragile (Re)-building of (new)
B
nascent endothelial vessels vessels after injury
MC Coagulation factors Hemostasis
repair vessel breaches via formation of fibrin
via re-endothelialization and platelet thrombus
by VEGF
SMC
EC
Platelets Fibrin attracts vascular cells
Coagulation factors
Fibrin stimulate vessel sprouting
Production of
extracellular matrix by HIF-1 and VEGF
(A) Initiation of coagulation by tissue factor/FVIIa sequentially generates FXa, thrombin, and fib-
rin—all essential for clot formation. Activation of PARs by thrombin stimulates platelet aggrega-
tion. Coagulation factors also induce angiogenic signaling in vascular cells. Arrows indicate interac-
tions between receptors and their ligands. (B) Possible coagulation factor involvement in angiogen-
esis and vessel stabilization. (Left) Fragile newly forming endothelial (EC) vessels are stabilized by
recruitment of mesenchymal precursor cells (MC), which differentiate into contractile smooth
muscle cells (SMC) and produce extracellular matrix (ECM). (Right) Upon vascular injury, coagula-
tion stops bleeding (hemostasis) through formation of a fibrin and platelet thrombus. Coincidently,
coagulation factors stimulate the repair of injured vessels and may contribute to the building of
new vessels by activating HIF-1 and releasing VEGF. Fibrin provides a provisional matrix for migrat-
ing vascular cells during the formation of new blood vessels.
How do all of these molecules, gener- tween distinct PARs on vascular cells may
ated during the initiation of coagulation, significantly expand the complexity and
trigger angiogenesis? Emerging evidence diversity of angiogenic signals. For exam-
suggests that tissue factor and FVIIa par- ple, PAR2 can be transactivated by
ticipate in angiogenic signaling through cleaved PAR1, implying that, even though
the involvement of tissue factor’s intracel- PAR2 is not capable of being activated by
lular tail (10). However, vascular develop- thrombin, it nonetheless may contribute to
ment is normal in embryos expressing a the thrombin response (6). Individual
truncated version of tissue factor without PARs have distinct activities—for exam-
the intracellular domain (11). It is proba- ple, only PAR2 is up-regulated by inflam-
ble that proteolytic activity of FVIIa, in- matory mediators in endothelial cells,
dependent of thrombin formation, is also whereas activation of PAR1 selectively
involved in angiogenic signaling. Indeed, leads to smooth muscle contraction.
recent evidence indicates that PAR2, al- Because fibrin- and platelet-dependent
though activated by trypsin and a mast hemostasis and angiogenesis are closely
SCIENCE VOL 293 31 AUGUST 2001 1603
 S C I E N C E ’ S C O M PA S S
65 intertwined, it has remained unclear normal vascular fragility is also apparent likely to contribute to pathological angio-
64 whether bleeding in embryos lacking tis- in embryos lacking angiopoietin-1, its genesis because overexpression of tissue
63 sue factor, PAR1, or other coagulation Tie2 receptor, and several other angio- factor promotes tumor angiogenesis. Final-
62 factors results from defective hemostasis genic molecules (9), the interaction be- ly, even though coagulation factors and, in
61 or blood vessel formation. Griffin et al. tween coagulation and these angiogenic particular, PARs, have not been a direct
60 now provide some insights by demon- molecules deser ves fur ther study. target of pro- or anti-angiogenic drug de-
59 strating that loss of PAR1 does not pre- Whether the vascular fragility in PAR1- velopment, they may become so in the fu-
58 vent vessel formation per se but rather deficient embryos results from defective ture. Building stable vessels with PAR ag-
57 impairs the stabilization and maturation thrombin or tissue factor/FVIIa/FXa sig- onists would improve perfusion of is-
56 of newly forming vessels, thereby causing naling remains to be determined. Indeed, chemic tissues, whereas destabilizing ves-
55 breaches and abnormal fragility in the tissue factor is involved in the stabiliza- sels with PAR antagonists may suppress
54 vessel walls (2). By switching on expres- tion of newly forming fragile vessels, be- tumor growth. The observations of Griffin
53 sion of PAR1 in endothelial cells, these cause loss of tissue factor causes vessel et al. should prime sufficient interest to
52 investigators were able to rescue PAR1- fragility owing to defective recruitment of ensure that these questions are answered in
51 deficient mouse embryos from bleeding pericytes (13). the near future.
50 to death. This demonstrates that activa- Considering the pleiotropic activity of
49 tion of PAR1 and its signaling pathway in thrombin on vascular cells and its ability References
48 endothelial cells is essential for vascular to trigger crucial angiogenic signaling by 1. S. R. Coughlin, Nature 407, 258 (2000).
2. C. T. Griffin et al., Science 293, 1666 (2001).
47 integrity. By stimulating changes in en- VEGF and HIF-α, why does loss of PAR1 3. P. Carmeliet, R. K. Jain, Nature 407, 249 (2000).
46 dothelial cell shape, mig ration, and impair stabilization but not growth of new 4. K. T. Preissner, P. P. Nawroth, S. M. Kanse, J. Pathol.
45 growth through enhancement of VEGF- vessels in the embryo? Even more impor- 190, 360 (2000).
44 5. P. Carmeliet, D. Collen, Thromb. Res. 91, 255 (1998).
dependent signaling, PAR1 may facilitate tant, to what extent do these findings in 6. P. J. O’Brien, M. Molino, M. Kahn, L. F. Brass, Oncogene
43 repair of vessel wall breaches and secure the embryo extrapolate to the adult, where 20, 1570 (2001).
42 vascular integrity. Although the Griffin angiogenesis contributes to, and coagula- 7. M. Nakanishi-Matsui et al., Nature 404, 609 (2000).
41 study, at first glance, seems to indicate tion factors are up-regulated in, numerous 8. L. V. Rao, U. R. Pendurthi, Trends Cardiovasc. Med. 11,
14 (2001).
40 that PAR1 affects only endothelial cells, disorders? Surviving PAR1-deficient mice 9. P. Carmeliet, Nature Med. 6, 389 (2000).
39 endothelial PAR1 may also indirectly af- exhibit normal re-endothelialization after 10. A. Siegbahn, Haemostasis 30, 41 (2000).
38 fect the recruitment, differentiation, inter- vascular injury, but we do not know 11. E. Melis et al., Biochim. Biophys. Res. Commun., in
37 press.
action, or stabilization of perivascular whether angiogenesis in pathological con- 12. M. Riewald, W. Ruf, Proc. Natl. Acad. Sci. U.S.A. 98,
36 cells (pericytes) by release of PDGF or ditions is impaired in mice with inactivat- 7742 (2001).
35 matrix proteinase. Considering that ab- ed PAR genes. Coagulation factors are 13. P. Carmeliet et al., Nature 383, 73 (1996).
34
33 PERSPECTIVES: SOCIAL SCIENCE AND ECOLOGY
32 people is) and the benefits of graph theory
31
30 Networking Tips for Social for delimiting nested networks in order to
better understand influences within com-
29 plex systems. The concept of cohesion
28
27
Scientists and Ecologists parallels that of “guilds” (3) or “tropho-
species” (4) in ecology, where organisms
26 Sean M. McMahon, Kevin H. Miller, Jim Drake that eat and are eaten by similar species
25 are treated as one group. Steven Borgatti
24 or the past 30 years, a subdiscipline computer science. Like social network (Boston College) and Martin Everett (Uni-
23
22
21
F of the social sciences known as social
network analysis has developed
structural models to analyze human inter-
analysis, analyses of trophic structure in
ecological communities and of energy
flow and nutrient transfer through ecosys-
versity of Greenwich) discussed the con-
cept and mathematical application of “reg-
ular equivalence,” an approach to social
20 actions (1). In social network analysis, tems incur the problem of how to concep- networks that provides a formal model
19 discrete mathematics and statistics are tualize and test interactions within these defining the notion of social roles. An ex-
18 combined with the emerging epistemolo- complex systems. The striking similarities ample of regular equivalents would be two
17 gy of complex systems to explore process- between social networks and biological doctors at different hospitals. Although
16 es and phenomena as diverse as the diffu- communities suggest that there exist con- they do not see the same patients, or inter-
15 sion of information through an organiza- straining or structuring forces common to act with the same suppliers, nurses, and
14 tion, the adoption of innovations in soci- both. Social and ecological networks also administrators, they have similar interac-
13 ety, and the spread of infectious disease in share the need to reduce the elements and tions with equivalent others, and thus play
12 a population. Scientists working on social interactions of the network to an order the same role. Furthermore, their equiva-
11 network analysis draw upon myriad disci- simple enough to analyze, yet complex lence is decided not by their work or cre-
10 plines: sociology, anthropology, psycholo- enough to reflect reality. dentials per se, but by the relationships
9 gy, geography, mathematics, statistics, and Simplifying complex system analysis they have with other members of the net-
8 was just one of the many topics discussed work. Joseph Luczkovich (East Carolina
7 S. M. McMahon and J. Drake are in the Complex Sys- at an NSF-sponsored workshop on net- University), an ecologist, demonstrated
6 tems Group, Department of Ecology and Evolutionary work theory and biocomplexity held at the how regular equivalence, when applied to
5 Biology, University of Tennessee, Knoxville, TN 37996, Duke University Marine Laboratory in ecological communities, can help ecolo-
4 USA. E-mail: seanmcm@utk.edu, jdrake@utk.edu K. North Carolina (2). Computer scientist gists partition species into groups that play
H. Miller is in the Coastal Resources Management
3 Program and Department of Biology, East Carolina Stephen Seidman (Colorado State Univer- the same roles even if, unlike trophic
2 University, Greenville, NC 27858, USA. E-mail: sity) explained the social science concept guilds, they do not consume the same prey
1 khm1212@mail.ecu.edu of “cohesion” (how tightly knit a group of or share the same predators.

1604 31 AUGUST 2001 VOL 293 SCIENCE www.sciencemag.org

 Clotting Factors Build Blood Vessels
Peter Carmeliet
Science 293, 1602 (2001);
DOI: 10.1126/science.1064981

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