Enhanced Vascular Smooth Muscle Calcium Sensitivity and Loss of Endothelial Vasodilator Influence Contribute to Myogenic Tone Development in Rat Radial Uterine Arteries during Gestation

Abstract

Uterine artery myogenic tone (MT) develops during pregnancy in hemochorial placentates such as rats and humans. The physiological reason for its appearance is not clear, and we reasoned that it may be a late pregnancy (LP) event in preparation for controlling hemorrhage during parturition. We also hypothesized that gestational increases in RhoAinduced vascular smooth muscle (VSM) calcium sensitivity are contributory and occur under the tonic influence of nitric oxide (NO). Second-order pre-placental radial arteries from early-pregnant (day 12, n = 5), mid-pregnant (day 16, n = 5) and LP (day 20, n = 20) rats were used in combination with arteriography, VSM calcium measurements, pharmacological RHO/Rho-associated protein kinase (ROCK) and nitric oxide synthase (NOS) inhibition, and Western blotting. A subgroup of LP animals (LP + LN; n = 5) treated with L-NAME from gestational days 10 to 20 were used to deter-mine the effects of NOS inhibition on MT and RhoA expression. MT was evident throughout pregnancy, but its expression in pressurized vessels was masked by endothelial NO-induced vasodilation during early gestation. RhoA protein expression was upregulated in LP and attenuated by in vivo NOS inhibition (as was MT). In vitro RHO/ROCK inhibition decreased MT in a concentration-dependent manner without reducing VSM calcium. In summary, pressure-dependent uterine artery tone increases with gestational age due to a combination of RhoA-mediated increases in VSM calcium sensitivity and a loss of endothelial NO influence.

The L-NAME mouse model of preeclampsia and impact to long-term maternal cardiovascular health

“…Although L-NAME is commonly directly applied to vessels in ex vivo studies (used for over 20 yr ( 76 )), few studies have explored the effect of administering L-NAME in vivo on vascular reactivity. One study showed that L-NAME administration impaired acetylcholine induced vasorelaxation in rat aortic rings ( 77 ) and another that L-NAME impaired myogenic tone of rat uterine radial arteries ( 78 ). However, it is understood that vascular adaptations in pregnancy are distinct between rats and mice ( 79 ), which may explain the discrepancy.…”

Perivascular Adipose Tissue and Uterine Artery Adaptations to Pregnancy

“…Myogenic tone is an intrinsic property of the vascular smooth muscle cells that enables them to constrict in response to an increase in perfusion pressure [58], maintaining blood flow in high perfusion organs, such as the pregnant uterus [59,60]. Pregnancy-induced changes in myogenic tone of uterine arteries are species-dependent and involve different intracellular mechanisms.…”

“…Similar to human myometrial arteries from late pregnant women, preplacental uterine radial arteries from late pregnant rats (Gestational Day 20, term = 21–22 days) showed greater myogenic tone than arteries from rats at mid‐gestation (Gestational Day 12). NOS inhibition significantly enhanced pressure‐dependent tone only in arteries from early pregnant (Gestational Day 12) but not from late pregnant (Gestational Day 20) rats [60]. In addition, uterine arteries from late pregnant rats had increased RhoA kinase expression [60] and a significant elevation of intracellular Ca 2+ ([Ca 2+ ] i ) [59].…”

“…NOS inhibition significantly enhanced pressure‐dependent tone only in arteries from early pregnant (Gestational Day 12) but not from late pregnant (Gestational Day 20) rats [60]. In addition, uterine arteries from late pregnant rats had increased RhoA kinase expression [60] and a significant elevation of intracellular Ca 2+ ([Ca 2+ ] i ) [59]. These data suggest that the role of molecular mediators of vascular smooth muscle contraction, including endothelium‐derived factors and Ca 2+ ‐dependent and ‐independent mechanisms, vary with gestational age.…”

Advanced Maternal Age Impairs Uterine Artery Adaptations to Pregnancy in Rats

“…The myogenic tone thus functions as an autoregulatory process to maintain constant blood flow to critical organs across varying blood pressures [ 9 ]. The myogenic tone was reported to be increased (human myometrial arteries and rat radial uterine arteries [ 10 , 11 , 12 , 13 , 14 , 15 ]) or decreased (mouse and guinea pig main uterine arteries [ 16 , 17 , 18 ]) with pregnancy. In addition to vascular function, the structure of arteries also determines their capacity for blood flow.…”