Conclusions

Endothelium and blood vessels carry out certain common core functions: Arteries and arterioles transport blood (oxygen and nutrients); capillaries regulate the exchange of oxygen, and other blood constituents to the underlying tissue; and veins drain the organs of carbon dioxide and metabolic by-products. Different vascular beds employ different strategies to accomplish these tasks. Moreover, each vascular bed—particularly at the level of the capillary—is tightly coupled to the local tissue environment. In the case of the heart, coronary blood flow is highly coupled to the metabolic needs of the cardiomyocytes and is protected by multiple "backup" systems, including the presence of collateral vessels. The microvascular endothelium of myocardial capillaries is exposed to a spatially and temporally regulated input of heart-specific signals—including those that arise from the cardiomyocyte and the hemodynamic forces associated with the cardiac cycle. The dynamic and malleable nature of the endothelium renders these cells vulnerable to pathophysiological changes in the composition of the extracellular milieu. The altered signal input may be transduced by the endothelial cell in ways that perpetuate or accentuate the underlying pathophysiology. Important goals for the future will be to understand how the endothelium contributes to cardiac microvascular disease, and how its privileged location and communication network within the local microenvironment can be exploited for therapeutic purposes.

Glossary

Endothelial cell activation: The phenotypic response of the endothelium to an inflammatory stimulus, usually consisting of some combination of procoagulant and proadhesive properties, and/or alteration in permeability. The criteria for activation depend on the location within the vascular tree.

Endothelial cell dysfunction: An endothelial cell phenotype that represents a net liability to the host. Common examples include coronary artery disease (local dysfunction) and sepsis (systemic dysfunction).

Input—output device: A device that senses the environment and responds in a way that is usually adaptive (function) or nonadaptive (dysfunction). Each endothelial cell behaves like an input-output device, coupling changes in the extracellular milieu (input) to alterations in phenotype (output) via nonlinear networks of intracellular signaling pathways.

Bibliography

Brutsaert, D. L. (2003). Cardiac endothelial-myocardial signaling: Its role in cardiac growth, contractile performance, and rhythmicity. Physiol. Rev. 83(1), 59-115. This is a comprehensive review of cardiac endothe-lium and the role for the environment in regulating endothelial phenotypes.

Carmeliet, P. (2003). Angiogenesis in health and disease. Nat. Med. 9(6), 653-660. This review provides an overview of differences in the molecular control of angiogenesis and arteriogenesis in the heart.

Rosenberg, R. D., and Aird, W. C. (1999). Vascular-bed-specific hemosta-sis and hypercoagulable states. N. Engl. J. Med. 340(20), 1555-1564. This article reviews the molecular basis for a cardiac-specific signaling pathway that involves cross-talk between microvascular endothelial cells and cardiomyocytes.

Stevens, T., Rosenberg, R., Aird, W., et al. (2001). NHLBI workshop report: Endothelial cell phenotypes in heart, lung, and blood diseases. Am. J. Physiol. Cell. Physiol. 281(5), C1422-C1433. This paper provides an update on endothelial cell heterogeneity in the heart, lung, and blood and includes a summary of the embryonic origin of the coronary endocardium.

Capsule Biography

Dr. Aird is Chief of the Division of Molecular and Vascular Medicine at the Beth Israel Deaconess Medical Center and is the Deputy Director of the institution-wide Center for Vascular Biology Research. Dr. Aird's laboratory focuses on understanding the spatial and temporal regulation of endothelial cell phenotypes. His work is supported by grants from the National Institutes of Health.

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