Impaired vascular remodeling in the yolk sac of embryos deficient in ROCK-I and ROCK-II

Abstract

Rho‐associated coiled‐coil‐forming protein serine/threonine kinase (ROCK) consisting of two isoforms, ROCK‐I and ROCK‐II, functions downstream of the small GTPase Rho for assembly of actomyosin bundles. To examine the role of ROCK isoforms in vivo, we previously generated and examined mice deficient in each of the two isoforms individually. Here, we further examined the in vivo role of ROCK isoforms by generating mice deficient in both isoforms. Cross‐mating of ROCK‐I+/−ROCK‐II+/− double heterozygous mice showed that all of the ROCK‐I−/−ROCK‐II−/− homozygous mice die in utero before 9.5 days post‐coitum (dpc) and ROCK‐I−/−ROCK‐II+/− homo‐heterozygous or ROCK‐I+/−ROCK‐II−/− hetero‐homozygous mice die during a period from 9.5 to 12.5 dpc, whereas mice of other genotypes survive until 12.5 dpc with the expected Mendelian ratio. All of the ROCK‐I+/−ROCK‐II−/− or ROCK‐I−/−ROCK‐II+/− mice showed impaired body turning and defective vascular remodeling in the yolk sac. Impairment of vascular remodeling was also observed in wild‐type embryos treated ex vivo with a ROCK inhibitor, Y‐27632. These results suggest that ROCK isoforms function redundantly during embryogenesis and play a critical role in vascular development.

Small G Proteins in the Cardiovascular System: Physiological and Pathological Aspects

“…This concept is in agreement with in vitro studies that provide evidence that RhoA and Rho-kinase need to be actively inhibited during endothelial tube lumen formation and tube maintenance events (96). The role of RhoA/Rho-kinase axis in the developmental angiogenesis was further supported recently by the observation that homozygous mice deficient in both isoforms of Rho-kinase (Rock1 Ϫ/Ϫ ;Rock2 Ϫ/Ϫ ) display defective vascular remodeling in the yolk sac and die in utero before E9.5 (208). These results also suggest a redundant role of Rho-kinase isoform functions in vascular development during embryogenesis.…”

Rho-Associated Kinase Activity Is Required for Proper Morphogenesis of the Inner Cell Mass in the Mouse Blastocyst1

“…Interestingly, this finding is consistent with a recent study of double knockout mice deficient in both Rock1 and Rock2 genes [56]. The double null mutant embryos can develop to the blastocyst stage but show lethality after implantation, as evidenced by the fact that the embryos are resorbed before E9.5, which is the stage when body turning into fetal position has normally completed [57].…”

Rho Kinases in Health and Disease: From Basic Science to Translational Research

“…A tight spatiotemporal regulation of ROCK activity in endothelial cells is essential for normal cell migration, lumen formation, and normal angiogenesis (Whitehead et al, 2009;Stockton et al, 2010;Davis et al, 2011). Defective vascular remodeling in the yolk sac and in utero death before embryonic day E9.5 of homozygous mouse embryos deficient in both isoforms of ROCK (Rock1 2/2 ; Rock2 2/2 ) confirm the role of ROCKs in developmental angiogenesis and suggest a redundant role of ROCK isoform functions in vascular development during embryogenesis (Kamijo et al, 2011).…”