Prostacyclin and its stable analogs play an important vascular protective role by promoting angiogenesis, but their role in arteriolar growth is unclear. Here, we examined the effect of
prostacyclin stable analog
carbaprostacyclin on arteriolar growth in mouse hindlimb
ischemia. Using an osmotic-controlled release system to continuously deliver
carbaprostacyclin or saline (control) to ischemic mouse hindlimbs for up to 14 days, we found that blood perfusion was significantly better at 7 and 14 days in
carbaprostacyclin-treated mice than in saline-treated mice. Microscopic examination of the microvasculature showed more morphological signs of arteriolar formation in
carbaprostacyclin- versus saline-treated legs. A double-blind, quantitative microcomputed tomography analysis indicated that
carbaprostacyclin-treated legs had markedly increased vascular volume and small- to medium-sized vessel numbers that correspond to decreased vessel separation. A
proteome profiler antibody array demonstrated that
carbaprostacyclin-treated ischemic muscles secreted significantly higher amounts of
acidic fibroblast growth factor and other
chemokines.
Conditioned media containing those secreted factors promoted smooth muscle cell growth and migration. Additionally, increased
acidic fibroblast growth factor protein levels were detected in smooth muscle cells and skeletal myotubes at different time periods after
carbaprostacyclin treatment. Furthermore, the selective peroxisome proliferation-activated receptor β/δ antagonist significantly suppressed
carbaprostacyclin-induced
acidic fibroblast growth factor protein production. Collectively, our data provide the first morphological and molecular evidence that local delivery of
carbaprostacyclin promotes vascular growth in hindlimb
ischemia, and that peroxisome proliferation-activated receptor β/δ signaling plays a critical role in inducing
acidic fibroblast growth factor expression.