James B. Hoying
Cardiovascular Innovation Institute, University of Louisville, USA
The final intent of microvascular regeneration is the re-establishment of an effective microcirculation within the target tissue. Successful, strategies for forming a microcirculation (i.e. a microvascular perfusion circuit) must address not only the derivation of new, individual microvessel elements, but also the organization of each element into an effective network. Indeed, numerous examples of tissue repair/regeneration in which perfusion is reduced even though microvessel density is elevated highlight the importance of this network topology aspect. The final, tissue-specific topology of a native microvasculature arises, in part, from an intrinsic plasticity and adaptability of microvessels. Using a unique microvascular regeneration approach, we have shown that immature neovessels formed via angiogenesis transition through a phase of instability necessary to the re-organization of neovessels within the network and specialization of each neovessel into a mature microvessel type (i.e. arteriole, capillary, and venule). Proper progression through this unstable phase depends on hemodynamic inputs. In addition, it's during this phase in which the angiogenesis-derived neovessels, which have lost the arterio-venous identity of their parent microvessels, re-acquire arterial, capillary, or venous specification, an activity critical to maturation of the microcirculation. Reflecting further the intrinsic adaptability of neovessels, the regenerated microcirculation can be functionally changed during its formation to reflect tissue-specific phenotypes. For example, inclusion of astrocyte precursor cells, brain cells that interact intimately with the native brain microcirculation, during the regeneration of the new microvasculature induces a blood-brain-barrier-like character to the new microcirculation as opposed to a more ubiquitous continuous-phenotype of the peripheral microvasculature. Taken together, our findings indicate that the topology and character of regenerated microvascular networks, as defined by arteriovenous identity, segment organization, and functionality, arises from considerable phenotypic and topological plasticity intrinsic to newly forming microvessels. Implied, regeneration strategies that constrain neovessel adaptation or seek to pre-determine microvascular outcomes may be problematic and result in dysfunctional microcirculations.