Background
Ameliorating critical limb ischemia (CLI), in part, relies on arteriogenesis and angiogenesis. We have shown that thrombospondin-5 (TSP5) is proangiogenic in vitro. The role of TSP5 in CLI and the differences between males and females are unknown. Blood flow recovery, arteriogenesis, and angiogenesis after limb ischemia is diminished (1) in TSP5-null mice compared with controls, and (2) in female compared with male TSP5 null-mice.
Methods
Fourteen- to 16-week-old wild-type (WT; C57Bl6) or TSP5-null male and female mice underwent left femoral artery ligation and transection (n = 6-9/group). Laser Doppler data were collected preoperatively, after ligation, and at humane killing (day 14). Blood flow recovery was expressed as a ratio of ischemic/nonischemic limb. Immunohistochemistry was performed using anti-α-smooth muscle actin on the vastus lateralis to quantify arteriogenesis and anti-CD31 on the gastrocnemius to quantify angiogenesis. Arteriole and capillary density were determined by vessel counts/5 high-power field. Data were analyzed by analysis of variance with post hoc testing, with a P values of less than .05 being significant.
Results
TSP5-null mice had decreased blood flow recovery in males (WT 0.85 ± 0.04 vs TSP5 0.48 ± 0.06; P < .001) and females (WT 0.63 ± 0.07 vs TSP5 0.36 ± 0.04; P < .01). No difference in flow recovery was seen between male and female TSP5 nulls (male 0.48 ± 0.06 vs female 0.36 ± 0.04; P < .14). Arteriogenesis was impaired in male TSP5 null mice (WT 3.91 ± 0.24 vs TSP5 2.6 ± 0.42; P < .02), but increased in females (WT 2.5 ± 0.26 vs TSP5 4.35 ± 0.73; P < .01). Angiogenesis was decreased in TSP5-null males (WT 10.9 ± 0.93 vs TSP5 7.03 ± 0.84; P < .01), but not females (WT 6.1 ± 0.50 vs TSP5 5.6 ± 0.80; P < .9). In contrast, flow recovery, angiogenesis, and arteriogenesis were decreased in WT females compared with WT males (P < .05).
Conclusions
Our findings suggest that TSP5 is relevant to vascular remodeling following hindlimb ischemia with a divergence in mechanism between males and females. TSP5 is necessary in males for arteriogenesis and angiogenesis. TSP5 in females may be suppressive of arteriogenesis and has no effect on angiogenesis. Further investigation into these sexually dimorphic adaptive processes may lead to specific targeted CLI treatments.
Article info
Publication history
Published online: June 10, 2022
22-VIRC-526-AHA-VDFootnotes
Author Disclosures: M. M. Rangel: Nothing to disclose; C. Bunn: Nothing to disclose; X. Wang: Nothing to disclose; X. Ding: Nothing to disclose; K. Maier: Nothing to disclose; V. Gahtan: Nothing to disclose
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© 2022 Published by Elsevier Inc.
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