Endothelin Type A Receptor Blockade is Beneficial Against Age‐Related Increased Cardiovascular Risk in Female Intrauterine Growth Restricted Offspring
Authors: Ariatti Allison M. , Coats Laura , Ojeda Norma , Intapad Suttira , Alexander Barbara T. 
Published: April 2020

Cardiovascular (CV) disease remains the leading cause of death in women. An important risk factor for CV disease is hypertension which is less controlled in women over 60 relative to men despite women being more compliant with therapeutic regimen. These findings imply sex‐specific processes may be involved. The prevalence of hypertension is greater in low birth weight women relative to normal birth weight counterparts by age 60. CV risk is also greater in low birth weight women after menopause suggesting that exposure to adverse influences during fetal life enhance the risk for CV disease in women as they age. The Alexander laboratory utilizes a rodent model of low birth weight or intrauterine growth restriction (IUGR) induced by placental insufficiency in the Sprague Dawley rat that result in increased mean arterial pressure (MAP) in female IUGR offspring by 12 months of age as well as premature cessation of estrous cyclicity indicative of early reproductive senescence. Low birth weight also increases the risk of earlier age at onset of natural menopause in women suggesting that this model of IUGR mimics facets of chronic health in low birth weight women. Yet, the etiology of increased blood pressure (BP) and CV risk linked to impaired fetal growth in women is unknown. The endothelin (ET‐1) system contributes to BP control with its physiological effects mediated via a balance between 2 receptors, endothelin type A (ETAR) and type B (ETBR). ET‐1 levels are elevated in women after menopause and the vasoconstrictor effects of ET‐1 are amplified suggesting that ET‐1 contributes to the increase in the prevalence of hypertension that develops after menopause. Thus, we hypothesized that ET‐1 is a primary contributor to the increase in MAP that develops by 12 months of age in female IUGR offspring. To test this hypothesis, female Control from sham operated dams and IUGR offspring from reduced uterine perfusion dams were treated with vehicle (Untreated) or an ETAR antagonist (Treated), atrasentan at a dose of 5 mg/kg per day via drinking water. MAP was measured via arterial catheter in conscious animals after 5 days of treatment. 24 hour metabolic studies were performed prior to ETAR blockade for measurement of urinary endothelin; kidneys were collected at the end of study for quantitation of ET‐1 and ET‐1 receptor expression. MAP was significantly decreased in Treated IUGR offspring (123±2 mmHg) compared to Untreated IUGR (142±4 mmHg)(p<0.05). Although MAP was significantly decreased in Treated Control offspring (128±6 mmHg) compared to Treated IUGR (p<0.05), MAP was not significantly reduced in Treated Control when compared to their Untreated Control counterparts (131±3 mmHg). Thus, these studies indicate that blockade of the ETAR is beneficial in reducing the increase in BP that develops in female IUGR suggesting blockade of ET‐1 may be a potential therapeutic target to lessen or prevent high BP and CV risk in low birth weight women as they age.

Support or Funding Information

HL143459, P20GM121334, P20GM104357, HL51971, T32HL105324