Physiological Capillary Regression is not Dependent on Reducing VEGF Expression

Abstract

Investigations into physiologically-controlled capillary regression report the provocative finding that microvessel regression occurs in the face of persistent elevation of skeletal muscle vascular endothelial growth factor-A (VEGF) expression. Thrombospondin-1 (TSP-1), a negative angiogenic regulator, is increasingly being observed to temporally correlate with capillary regression, suggesting that increased TSP-1 (and not reduction in VEGF per se) is needed to initiate, and likely regulate, capillary regression. Based on evidence being gleaned from physiologically-mediated regression of capillaries, it needs to be recognized that capillary regression (and perhaps capillary rarefaction with disease) is not simply the reversal of factors used to stimulate angiogenesis. Rather, the conceptual understanding that angiogenesis and capillary regression each have specific and unique requirements that are biologically constrained to opposite sides of the balance between positive and negative angioregulatory factors may shed light on why anti-VEGF therapies have not lived up to the promise in reversing angiogenesis and providing the cure that many had hoped toward fighting cancer. Emerging evidence from physiological controlled angiogenesis suggest that cases involving excessive or uncontrolled capillary expansion may be best treated by therapies designed to increase expression of negative angiogenic regulators, whereas those involving capillary rarefaction may benefit from inhibiting negative regulators (like TSP-1).

Enterococcus faecium strain R30 increases red blood cell velocity and prevents capillary regression in the soleus of hindlimb‐unloaded rats via the eNOS/VEGF pathway

“…In addition, the levels of eNOS and VEGF protein were not different in each HU group compared to its saline control. These results are consistent with our earlier findings in the soleus muscle of HU rats and with the report of Olfert reviewing that capillary regression is not dependent on reducing VEGF expression. Furthermore, Egginton has reviewed that dynamic molecular events related to capillary regression occur within the first week.…”

“…In contrast, a reduction in the capillary network leads to exercise intolerance . A chronic decrease in neuromuscular activity, that is, a decrease in activation and/or loading, leads to capillary regression in skeletal muscles, especially in muscles having a high percentage of slow, oxidative fibers such as the soleus muscle . The capillary regression appears to be an adaptation to a reduction in blood flow to the skeletal muscles caused by a decrease in oxidative demand with decreased neuromuscular activity .…”

Skeletal muscle performance in metabolic disease: Microvascular or mitochondrial limitation or both?

“…In some respects, the mechanistic bases of the evolving rarefaction of the microvascular network parallels that for the impairments to vascular tone regulation, as there is compelling evidence that the pro‐oxidant and pro‐inflammatory conditions that accompanies metabolic disease are associated with changes to vasoactive metabolite bioavailability that may be an initiating factor to microvessel loss . Taken in combination with multiple other mechanistic pathways that have been implicated in contributing to the loss of microvessels with metabolic disease, this area of research clearly remains one of considerable unknown; but which is also with outstanding potential for therapeutic benefit.…”

Ultrastructure of Skeletal Muscles in Mice Lacking Muscle‐Specific VEGF Expression

“…Anti‐angiogenic factors, such as thrombospondin‐1, also work to oppose VEGF activity (Olfert et al, ; Malek and Olfert, ). However, analysis of the relationship between angiogenic and anti‐angiogenic factors is hampered by the fact that their interactions do not seem to be based on a rigid stochastic relationship, and may vary in the context of the microenvironment (Olfert, ).…”