Current Pharmaceutical Biotechnology - Volume 8, Issue 1, 2007

The development and remodeling of vessels is a crucial process in many physiological and pathophysiological processes making it topic of in-depth research in laboratories all around the world. Vascular occlusive diseases as well as malignant tumors are head of death causing aliments in industrialized countries. The notion that tumor angiogenesis may have therapeutic implications in the control of tumor growth was already introduced 1971. This special issue of Current Pharmaceutical Biotechnology contains in depth reviews on latest and most important developments in therapeutic strategies aiming to modulate vascular growth in terms of angiogenesis and arteriogenesis. Up to date reviews on maintenance and function of microcirculatory processes as well as on development of tissue engineered vascular grafts are supplied. Finally, the issue is round by an article containing some critical aspects on the potential of stem cells in terms of clinical application. In the past decade, many angiogenesis inhibitors have been developed for clinical use in oncology. Since angiogenesis inhibitors are relatively less toxic than conventional chemotherapy and have a lower risk of drug resistance “anti-angiogenic chemotherapy” has become a novel approach in cancer therapy. However, the encouraging results of pre-clinical studies could not fully meet the high expectations at bed side making further studies necessary. In this issue W.W. Kilarski & A. Bikfalvi focus on screening systems used to investigate the mechanisms of tissue neovasculariziation and recent progresses in vessel targeted tumor therapy. Whereas it is the aim of scientists working in the field of tumor development to block angiogenesis, others are interested in processes of vascular function and maintenance under normal physiological conditions. Small arteries and arterioles play a key role in regulation organ blood flow. Striking differences with respect to behavior and sensitivity for metabolic or mechanical stimuli between arterioles of different size have been reported. Endothelial cells of muscular vessels crucially contribute to the control of vascular tone by the release of autocaids like endothelium-dependent hyperpolarizing factors (EDHFs). The special features and properties of small arteries and microcirculatory vessels with respect to endothelium are highlighted by the article of C. de Wit & S.E. Woelfle. The review by C. Kupatt stresses the role of the microcirculation in vascular occlusive diseases. He comes up with the concept that therapeutically induced angiogenesis, i.e. the sprouting of capillaries, may result in a backward signaling triggering the growth of blood supplying collateral arteries. It is known for many years that collateral arteries grow spontaneously as an adaptive response around arteries with progressive stenosis. Hypoxia, the most important stimulus for capillary sprouting is not required for arteriolar growth. However, it is more than a hypothesis that newly formed capillaries may cause the growth of upstream-located arterioles satisfying the oxygen and nutrient demand of ischemic tissue - in particular when keeping in mind that arteries supplying blood to a growing tumor also increase in diameter and size. The term arteriogenesis, defining the growth of pre-existing arteriolar connections into true collateral arteries was introduced by W. Schaper. With his studies on the growth of natural bypasses he opened a new field in research. The article by M. Heil & W. Schaper does not only describe the basic mechanisms of collateral artery growth but provides information about the most recent findings. The review gives insight into the prominent role of fluid shear stress causing an activation of arterioles as well as an attraction and extravasation of monocytes presenting growth factor and cytokine producing micro-factories. However, the role of individual growth factors as master regulators of arteriogenesis was overestimated for a long time as shown by disappointing results of clinical studies. Collateral artery growth is a multi-factorial process requiring a well-defined action of biomolecules in terms of time and space. Unless it is not investigated how the process triggering mechanical stress, the fluid shear stress, is translated into the biological response, even approaches with cell therapies based on paracrine acting factors will only result in the support of collateral artery growth but will never be able to induce arteriogenesis de novo. One discipline en vogue is the induction of growth of natural bypasses, the other one the development of tissue engineered vascular grafts. G.R. and J.H. Campbell present fascinating results of this new discipline. Synthetic vascular grafts were already introduced several decades ago. However, they are limited to high-flow low resistance conditions........

Angiogenesis is a developmental process that also plays the central role in adults during the female menstruation cycle, wound healing and neoplastic growth and metastasis. Ideally, blocking neovessel growth starves the developing tumor and induces tumor regression. Restricting the vascular ingrowth into the tumor might have adverse effect on drugs targeting the tumor. Nevertheless, anti-VEGF treatment of the neoplastic diseases when combined with chemotherapy significantly increases median survival in treated patients. This suggests alternative mechanisms of anti-angiogenesis therapy. A number of molecules that are in current clinical trials have been identified using angiogenesis models. However, current angiogenesis models have advantages and inconvenience and conclusion drawn upon their use should be interpreted with caution. Thus, it is necessary to optimize existing models and to develop new ones that take into account the complexity of the angiogenic process as it happens in many angiogenesis-related diseases and in particular in cancer.

Arterioles within the microcirculation control organ blood flow and represent the main peripheral resistance within the circulation. However, larger vessels with a diameter of more than 150 m are mostly used to study vascular behavior. Although arterioles have features in common with these conducting vessels, they exhibit distinct properties and the contribution of different pathways to constriction or relaxation varies with vessel size. This is especially the case for endothelium-dependent relaxations, which occur in response to mechanical stimuli (e.g. blood flow) and agonists. Autacoids released from the endothelium include nitric oxide, prostaglandins and an endothelium-derived hyperpolarizing factor (EDHF). Whereas nitric oxide is dominant in larger vessels, the importance of EDHF increases with decreasing vessel size. Its chemical nature is still a matter of debate and different substances have been identified to act as an EDHF in different vascular beds, e.g. epoxyeicosanoids, potassium ions, anandamide, hydrogen peroxide or C-type natriuretic peptide. Despite this heterogeneity of proposed factors it is unclear if such a factor indeed exists in all vessels since the hyperpolarization of vascular smooth muscle has been proposed to be induced by simple current transfer from the adjacent endothelium. For this to occur the cells need to be electrically coupled and this requirement is fulfilled by gap junctions which are composed of connexins forming intercellular channels. Aside from myoendothelial coupling gap junctions also interconnect endothelial cells thus creating a functional unit, which efficiently synchronizes cellular behavior within the arteriolar tree of the microcirculation.

In this review, the compartments of the vasculature will be discussed with respect to their potential contribution to the build-up of a differentiated and functionally meaningful vessel system. Chronic ischemia of muscle tissue results in microvessel rarification, which represents a potential therapeutic target, given the viability of the parenchyma. In particular, a chain of microcirculatory events will be described which - after specific endothelial activation by growth factors - enhances capillary and microcirculatory vessel formation, Backward signalling is introduced as potential mechanism to induce collateral growth, recruiting pre-existent macrovessel networks for blood supply to the increased microcirculatory cross sectional area. Potential signal cascades will be discussed.

The compensatory growth of blood vessels after major arterial occlusions has been termed arteriogenesis. Although having some characteristics in common with angiogenesis, marked differences between both forms of vascular growth exist relating to triggers, underlying mechanisms and physiologic effects. Arteriogenesis describes the remodelling of small interconnecting arterial anastomoses with almost no net blood flow to large functional arteries. It has been shown that growth of these collateral arteries is triggered by physical forces, but does not require hypoxia as a stimulus. In this review we describe an animal model which we used to characterize the role of fluid shear stress for arteriogenesis. Fluid shear stress initiates the activation of endothelial cells and modulates processes which control attraction of circulating cells to the collateral wall. Monocytes were shown to have a pivotal role during arteriogenesis. After entering the vascular wall they function as micro-bioreactors producing cytokines and thereby controlling cell proliferation and remodelling. Furthermore, cell proliferation coincides with the transient dismantling of extracellular structures such as the elastic lamina which is required to provide space for the increasing number of wall cells. After the re-arrangement of wall structures collaterals with large calibres represent functional arteries with the ability to compensate blood flow deficits caused by arterial occlusions. It is therefore questionable, whether there is also a form of de novo collateral artery growth with physiologic relevance.

Vascular bypass grafting is a commonly performed procedure for ischemic heart disease and peripheral vascular disease. However, approximately one in fourteen patients do not have suitable autologous arteries or veins available for grafting. Synthetic vascular grafts were introduced in the 1960s to overcome these problems, but while they perform adequately in high-flow, large-diameter vessel settings they are generally not suited to low-flow, small-diameter vessels. Tissue engineering is a relatively new discipline that offers the potential to create replacement structures from autologous cells and biodegradable polymer scaffolds. Because tissue engineering constructs contain living cells, they may have the potential to grow, self-repair, and self-remodel. Therefore, recently there has been much interest in the use of this technique to produce low-flow small-diameter arteries. The latest and most exciting developments in this area involve the use of multipotent stem cells as a cell source for tissue engineering of vascular grafts (both in vivo and in vitro).

There is considerable interest in biological sources for replacement, repair, as well as vascularization of tissue. The remarkable properties of blood stem cells encourage interest in their therapeutic potential. But what are these properties, and how do they influence their clinical potential and the advisability of stem cell use as a therapeutic resource? Rational assessment of the significance of in vitro and animal in vivo data should precede the rush from the bench to the bedside. Basic stem cell research is rife with examples where the truth of the subsequently demonstrated mechanism is stranger than the initial interpretation proved fiction. This review will assess tissue contribution by different blood related stem cells, differing possible mechanisms underlying observed repair phenomena, and consider the potency and pitfalls of stem cell therapeutics.