Vascular growth in health and disease

Abstract

Vascular growth forms the first functional organ system during development, and continues into adult life, wherein it is often associated with disease states. Genetically determined vasculogenesis produces a primary vascular plexus during ontogenesis. Angiogenesis, occurring, e.g., in response to metabolic stress within hypoxic tissues, enhances tissue capillarization. Arteriogenesis denotes the adaptive outgrowth of pre-existent collateral arteries to bypass arterial stenoses in response to hemodynamic changes. It has been debated whether vasculogenesis occurs in the adult, and whether or not circulating progenitor cells structurally contribute to vessel regeneration. Secondly, the major determinants of vascular growth - genetic predisposition, metabolic factors (hypoxia), and hemodynamics - cannot be assigned in a mutually exclusive fashion to vasculogenesis, angiogenesis, and arteriogenesis, respectively; rather, mechanisms overlap. Lastly, all three mechanisms of vessel growth seem to contribute to physiological embryogenesis as well as adult adaptive vascularization as occurs in tumors or to circumvent arterial stenosis. Thus, much conceptual and terminological confusion has been created, while therapies targeting neovascularization have yielded promising results in the lab, but failed randomized studies when taken to the bedside. Therefore, this review article aims at providing an exact definition of the mechanisms of vascular growth and their contribution to embryonic development as well as adult adaptive revascularization. We have been looking for potential reasons for why clinical trials have failed, how vitally the application of appropriate methods of measuring and assessment influences study outcomes, and how relevant, e.g., results gained in models of vascular occlusive disease may be for antineoplastic strategies, advocating a reverse bedside-to-bench approach, which may hopefully yield successful approaches to therapeutically targeting vascular growth.

Keywords: angiogenesis; arteriogenesis; vascular growth; vasculogenesis.

Figure 1

Vasculogenesis, angiogenesis, and arteriogenesis. During vasculogenesis (A), (hem-) angioblast precursors form blood islands (a), which subsequently differentiate into primary ECs (b), and early blood cells (c). The resulting primary vascular plexus (d) matures into a secondary vessel network (e). Angiogenesis (B) denotes the growth of capillaries, mostly in response to a lack in sufficient tissue supply with oxygen and nutrients that is signaled by a growth factor gradient (B). Capillary sprouts (f) grow from pre-existent vessels (g) in the direction of a growth factor gradient (e.g., VEGF) that is sensed by a tip cell (h) and followed by a vascular stalk (i) that subsequently lumenizes. Arteriogenesis describes the outgrowth of pre-existent arteriolar collaterals which then bypass an arterial stenosis (C). Atherosclerotic occlusion of a major conductance artery induces a pressure gradient between the collateral stem region (k) (approx. 100 mmHg) and the reentry zone (l) (approx. 25 mmHg), followed by a redistribution of perfusion, an increase in collateral flow and a subsequent outgrowth of the collateral arteriole of typical corkscrew-like morphology (m).

Figure 2

The tumor and the embryo. Rapid cell division leads to exponential tissue growth both during the growth of the mammalian embryo as well as in malignant tissues. Basic mechanisms of vascular growth occur both during normal development and tumor growth: vessel growth is promoted by the expression of angiogenic factors. When adequate oxygenation can no longer be warranted by diffusion, hypoxia, in addition, activates the angiogenic cascade. With the onset of flow, hemodynamics shape the developing vasculature.

Figure 3

Adaptive vascular growth in peripheral arterial disease (PAD). The pathophysiology of PAD is a suitable example of the interplay of different mechanisms partaking in adaptive vascular growth. Arterial inflow is usually compromised by a proximal (iliac or femoropopliteal) stenosis of one of the arteries that supply the lower extremity. Ischemia endangers and damages the distal (infrapopliteal) region. Hypoxia in the lower leg triggers an angiogenic response in the border zone of the ischemic tissue, which, however, cannot compensate for the loss of pulsatile arterial inflow. If sufficient collateral arterioles are present to circumvent the proximal stenosis, however, an increase in flow triggers their outgrowth, developing a biological bypass through arteriogenesis.

Figure 4

Tumor arteriogenesis/angiogenesis. Malignant neoplasms often critically depend on the development of an autonomous vascular system, which differs from physiological vascular tissue. Tumor vessels are devoid of a conventional arterial–venous hierarchy, unevenly distributed, often irregularly enlarged (a), leaky and often insufficient. Even in vascularized tumors, hypoxic regions develop (shaded areas). Interestingly, however, some tumor vessels share features of growing collateral arterioles in arteriogenesis, examples being their tortuosity (b) and the presence of perivascular macrophages (c). On a cellular and subcellular level, basement membrane degradation, SMC dedifferentiation, and growth factor profiles further indicate tumor arteriogenesis.