Disregulation of vascular growth (angiogenesis) underlies many diseases that include cancer, diabetes, and arthritis. Existing models of angiogenesis in vitro are important experimental tools, but do not reproduce in vivo-like angiogenesis from a """"""""parent"""""""" vessel filled with flowing blood. We propose to develop an advanced model of angiogenesis in vitro comprised of tissue-engineered bioartificial microvessels (BMVs) containing flowing luminal fluid and sprouting endothelial cell (EC) capillaries into a supportive gel of extracellular matrix. BMVs will be constructed by culture of ECs around a micro-diameter mandrel whose ends fit closely into polymer micro-tubing. Extraction of the mandrel leaves a tube of ECs which is perfused with nutritive media.
Aim 1 evaluates the influence of BMV diameter and rate of luminal flow on sprout formation. Also, composite BMVs (ECs surrounded with vascular smooth muscle cells [SMCs]) will be generated. We hypothesize that a proportion of EC capillaries from composite BMVs will be reinforced by SMCs to form artery- or vein-like conducting vessels.
In Aim 2, two adjacent BMVs will be induced to sprout a network of interconnected capillaries. We propose that induction of a pressure gradient between the BMVs will cause fluid to flow between the BMVs via the capillary network, simulating a capillary bed in vivo with arterial and venous connections. We believe our novel model will have a major impact on angiogenesis research and treatment of important angiogenesis-mediated diseases. Moreover, the model has a significant potential to be translated into microvascular systems for artificial tissues and organs. We consider our research program to be ideally suited to the R21 mechanism.
