The Implications of a New Microvascular Paradigm

Since the time of Malpighi in the late 17th century, scientists have understood capillary networks to consist of a unique class of tiny "hair-like" microvessels linking arteri-oles to venules. Part of what distinguished capillaries operationally from all other vessel types was that they were neither arterial nor venous and could therefore function as a vascular crossroads for gas and metabolite exchange at the tissue level. In the late 1970s and early 1980s, however, a series of studies out of Czechoslovakia on enzyme histo-chemistry began to challenge this long-standing presumption of capillary arterial-venous neutrality. In 1979, Lojda realized that because the enzyme alkaline phosphatase his-tochemically stained arterioles, and dipeptidylpeptidase IV (DPPIV) highlighted venules, staining for both of these enzymes together would help illuminate the entire capillary bed [16]. With this new staining method, Lojda was able to divide the capillary bed histologically into three distinct portions—an alkaline phosphatase section, a DPPIV section, and a third "transitional" zone in which both enzymes were present—revealing for the first time molecular differences within the microvasculature. Throughout the 1980s and early 1990s, a handful of studies revealed additional evidence of capillary heterogeneity with even more molecular markers, but these markers only lasted during specific windows of development. Not until the late 1990s did Ephrin-B2 prove to be the first reliable molecular marker of arterial identity from the largest down to the smallest vessels and persisting from development into adulthood. Much like Lojda's enzymes, Ephrin-B2 even more clearly maps out specific subsets of capillaries as arterial versus venous, providing the strongest challenge yet to the long-standing idea of capillaries as its own class of nonarterial, nonvenous blood vessel.

The new picture that is now emerging of microvascular identity is one of distinct arterial and venous microcirculations. These circulations are defined by the differential expression of molecular markers such as Ephrin-B2, which delineate an arterial continuum from arteries to arterioles, all the way down to corresponding microarterial capillary seg ments, and a venous continuum extending from veins to venules to corresponding microvenous capillary segments. These continuums display their own unique genetic, morphologic, and, perhaps, functional identities, and raise a host of new questions for the study of vascular biology and treatment of many human diseases: Why, for instance, do activated immune cells in the blood escape only through postcapillary venules and not through arterioles? Many vas-culitic processes, on the other hand, exhibit specific arterial versus venous predispositions for the site of inflammation. Both giant cell and Takayasu's arteritis, for instance, occur only in large arterial vessels, and Kawasaki's disease in medium-sized arteries, but the many small-vessel vasculitic processes, such as microscopic polyangiitis and Wegener's granulomatosis, have much less exclusive propensities. Would more directed studies of these many vasculitic processes reveal any segregration between microarterial and microvenous capillary segments and perhaps provide new clues to their mysterious pathogenic processes? In genetic disorders such as CADASIL, where mutations in Notch-3 lead to migraines, mood changes, strokes, and, ultimately, vascular dementia, why are only small arterioles affected? Are there any corresponding syndromes defined by defects in the genes of the venous microcirculation? And as the tumor microvasculature appears to consist of roughly half microarterial and half microvenous vessels, how important in the end is arterial and venous identity in forming a functioning tumor vasculature? Similarly, what would happen if either the arterial or venous development of the tumor vas-culature were blocked? And do chemotherapeutic or anti-angiogeneic agents specifically target the arterial or venous microcirculations? Research into Ephrins is providing the first window into answering these questions.

Much like Malpighi's microscopy and its ability to reveal an entire class of vessels that even William Harvey did not imagine, the study of Ephrins has begun to serve as the first example of a 21st-century molecularly-guided microscopy powerful enough to reveal unexpected heterogeneity within even Malpighi's own capillary microvessels. The missing link in Harvey's circuit appears to be defined neither by pores, nor even liminal capillaries, but rather by "microarteries" and "microveins" bridging together distinct arterial and venous circulations.

References

1. Harvey, W. (1958). Exercitatio Anatomica DeMotu Cordis Et Sanguinis in Animalibus. Trans. Chauncey D. Leake. Springfield: Charles C. Thomas.

2. Malpighi, M. (1929). "Malpighi's 'De Pulmonibus.'" Trans. James Young. Proc. Royal Soc. Med., Hist. Med. 1, 1—11. One of the only English translations of the Italian microscopist's famous 1661 manuscript, in which he first revealed the existence of capillary microvascular networks. It takes the form of two letters to his long-time mentor in Pisa.

3. Hirai, H., Maru, Y., Hagiwara, K., Nishida, J., and Takaku, F. (1987). A novel putative tyrosine kinase receptor encoded by the Eph gene. Science 238, 1717-1720.

4. Drescher U. (2002). Eph family functions from an evolutionary perspective. Curr. Opin. Genet. Dev. 12, 397-402.

5. Himanen, J. P., Rajashankar, K. R., Lackmann, M., Cowan, C. A., Henkemeyer, M., and Nikolov, D. B. (2001). Crystal structure of an Eph receptor-ephrin complex. Nature 414, 933-938.

6. Wilkinson, D. G. (2001). Multiple roles of Eph receptors and ephrins in neural development. Nat. Rev. Neurosci. 2, 155-164.

7. Murai, K. K., and Pasquale, E. B. (2002). Can Eph receptors stimulate the mind? Neuron 33, 159-162.

8. Folkman, J. (1971). "Tumor Angiogenesis: Therapeutic Implications." New England Journal of Medicine 285(21), 1182-1186.

9. Wang, H. U., Chen, Z. F., and Anderson, D. J. (1998). Molecular distinction and angiogenic interaction between embryonic arteries and veins revealed by Ephrin-B2 and its receptor Eph-B4. Cell 93, 741-753. The first report of the functional role of a member of the Ephrin family during developmental angiogenesis, and of the expression of Ephrin-B2 in endothelial cells of developing arteries but not veins.

10. Gerety, S. S., Wang, H. U., Chen, Z. F., and Anderson, D. J. (1999). Symmetrical mutant phenotypes of the receptor EphB4 and its specific transmembrane ligand Ephrin-B2 in cardiovascular development. Molecular Cell. 4, 403-414.

11. Gerety, S. S., and Anderson, D. J. (2002). Cardiovascular ephrinB2 function is essential for embryonic angiogenesis. Development 129, 1397-1410.

12. Pandey, A., Shao, H., Marks, R. M., Polverini, P. J., and Dixit, V. M. (1995). Role of B61, the ligand for the Eck receptor tyrosine kinase, in TNF-alpha-induced angiogenesis. Science 268, 567-569.

13. Brantley, D. M., Cheng, N., Thompson, E. J., Lin, Q., Brekken, R. A., Thorpe, P. E., Muraoka, R. S., Cerretti, D. P., Pozzi, A., Jackson, D., Lin, C., and Chen, J. (2002). Soluble Eph A receptors inhibit tumor angiogenesis and progression in vivo. Oncogene 21, 7011-7026.

14. Shin, D., Garcia-Cardena, G., Hayashi, S., Gerety, S., Asahara, T., Stavrakis, G., Isner, J., Folkman, J., Gimbrone, M. A. Jr., and Anderson, D. J. (2001). Expression of EphrinB2 identifies a stable genetic difference between arterial and venous vascular smooth muscle as well as endothelial cells, and marks subsets of microvessels at sites of adult neovascularization. Dev. Biol. 230, 139-150. This in-depth study of Ephrin-B2 expression in endothelial and vascular smooth muscle cells of the adult mouse vasculature provides the first demonstration that quiescent as well as remodeling capillaries possess arterial and venous identities of their own.

15. Gale, N. W., Baluk, P., Pan, L., Kwan, M., Holash, J., DeChiara, T. M., McDonald, D. M., and Yancopoulos, G. D. (2001). Ephrin-B2 selectively marks arterial vessels and neovascularization sites in the adult, with expression in both endothelial and smooth-muscle cells. Dev. Biol. 230, 151-160.

16. Lojda, Z. (1979). Studies on dipeptidyl (amino) peptidase IV (glycyl-proline napththylamidase). II. Blood Vessels. Histochemistry 59, 153-166.

Capsule Biographies

Dr. Garcia-Cardena is an Assistant Professor of Pathology at Harvard Medical School and the Director of the Laboratory for Systems Biology at the Center for Excellence in Vascular Biology, Brigham and Women's Hospital, Boston, Massachusetts.

Jeffrey M. Gelfand is a medical student at Harvard Medical School and a member of Dr. Garcia-Cardena's Laboratory.

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