Mechanisms of Vessel Regression: Toward an Understanding of the Resolution of Angiogenesis

Abstract

Physiological angiogenesis refers to a naturally occurring process of blood vessel growth and regression, and it occurs as an integral component of tissue repair and regeneration. During wound healing, sprouting and branching results in an extensive yet immature and leaky neovascular network that ultimately resolves by systematic pruning of extraneous vessels to yield a stable, well-perfused vascular network ideally suited to maintain tissue homeostasis. While the molecular mechanisms of blood vessel growth have been explored in numerous cell and animal models in remarkable detail, the endogenous factors that prevent further angiogenesis and control vessel regression have not received much attention and are largely unknown. In this review, we introduce the relevant literature from various disciplines to fill the gaps in the current limited understanding of the major molecular and biomechanical inducers of vascular regression. The processes are described in the context of endothelial cell biology during wound healing: hypoxia-driven activation and sprouting followed by apoptosis or maturation of cells comprising the vasculature. We discuss and integrate the likely roles of a variety of endogenous factors, including oxygen availability, vessel perfusion and shear stress, intracellular negative feedback mechanisms (Spry2, vasohibin), soluble cytokines (CXCL10), matrix-binding proteins (TSP, PEDF), protein cleavage products (angiostatin, vasostatin), matrix-derived anti-angiogenic peptides (endostatin, arresten, canstatin, tumstatin), and the biomechanical properties of remodeling the extra-cellular matrix itself. These factors aid in the spatio-temporal control of blood vessel pruning by inducing specific anti-angiogenic signaling pathways in activated endothelial cells, pathways which compete with pro-angiogenic and maturation signals in the resolving wound. Gaining more insight into these mechanisms is bound to shed light on unresolved questions regarding scar formation, tissue regeneration, and increase our understanding of the many diseases with angiogenic phenotypes, especially cancer.

Key endothelial cell angiogenic mechanisms are stimulated by the circulating milieu in sickle cell disease and attenuated by hydroxyurea

“…36,37 VEGF-D is essential for hypoxia-driven vascular development, 37 and PlGF enhances VEGF-stimulated angiogenesis under pathological conditions. 38 Anti-angiogenic molecules, such as the matrix-derived peptide, endostatin, and the matrix-binding protein, TSP-2, are important for tissue repair and regeneration, since they prune superfluous vessels forming a stable, well-perfused vascular network; 39 however, neither endostatin nor TSP-2 concentrations were altered in SCA patients not on hydroxyurea. Vasoocclusive events in SCD result in the occurrence of tissue ischemia, generating hypoxic conditions, EC activation, inflammatory events and the up-regulation of endothelial HIF-1, 40 known to induce the transcription of genes that drive angiogenesis, including VEGF.…”

Molecular mechanisms of neoplasia

“…Angiostatin inhibits angiogenesis by reducing proliferation as a result of extending the G 0 resting phase in the cell cycle [29] and disrupts normal functioning of the connections between endothelial cells, thereby inducing apoptosis. Reducing tumour vascularization significantly increases the level of neoplastic cell apoptosis [30]. The antiangiogenic action of angiostatin makes it possible to be used in antineoplastic therapy [30].…”

“…Reducing tumour vascularization significantly increases the level of neoplastic cell apoptosis [30]. The antiangiogenic action of angiostatin makes it possible to be used in antineoplastic therapy [30]. In turn, thrombospondin 1 is an extracellular glycoprotein that inhibits the proliferation and migration of endothelial cells as a result of interaction with CD36 on the surface of these cells.…”

“…As wydłużenia fazy spoczynku G 0 w cyklu komórkowym [29] i zaburza prawidłowe funkcjonowanie połączeń pomiędzy komórkami śródbłonka, indukując tym samym apoptozę. Zmniejszenie unaczynienia guza znacząco podnosi poziom apoptozy komórek nowotworowych [30]. Antyangiogenne działanie angiostatyny stwarza możliwość wykorzystania jej w terapii antynowotworowej [30].…”

“…Zmniejszenie unaczynienia guza znacząco podnosi poziom apoptozy komórek nowotworowych [30]. Antyangiogenne działanie angiostatyny stwarza możliwość wykorzystania jej w terapii antynowotworowej [30]. Z kolei trombospondyna 1 to pozakomórkowa glikoproteina, która hamuje proliferację i migrację komórek śródbłonka w wyniku wytworzonej interakcji z CD36 na powierzchni tych komórek.…”