Mechanisms underlying developmental programming of elevated blood pressure and vascular dysfunction: evidence from human studies and experimental animal models

Abstract

Cardiovascular-related diseases are the leading cause of death in the world in both men and women. In addition to the environmental and genetic factors, early life conditions are now also considered important contributing elements to these pathologies. The concept of 'fetal' or 'developmental' origins of adult diseases has received increased recognition over the last decade, yet the mechanism by which altered perinatal environment can lead to dysfunction mostly apparent in the adult are incompletely understood. This review will focus on the mechanisms and pathways that epidemiological studies and experimental models have revealed underlying the adult cardiovascular phenotype dictated by the perinatal experience, as well as the probable key causal or triggering elements. Programmed elevated blood pressure in the adult human or animal is characterized by vascular dysfunction and microvascular rarefaction. Developmental mechanisms that have been more extensively studied include glucocorticoid exposure, the role of the kidneys and the renin-angiotensin system. Other pathophysiological pathways have been explored, such as the role of the brain and the sympathetic nervous system, oxidative stress and epigenetic changes. As with many complex diseases, a unifying hypothesis linking the perinatal environment to elevated blood pressure and vascular dysfunction in later life cannot be presumed, and a better understanding of those mechanisms is critical before clinical trials of preventive or 'deprogramming' measures can be designed.

The Clinical Importance of Nephron Mass

“…123 In a larger study of 19-year-olds who were very preterm, stratified by weight for gestational age, birth weight correlated negatively with serum creatinine and albuminuria and positively with GFR. 124 These results are consistent with those of others, but as has been shown in animal studies, pro- Renal dysfunction Increased renal vascular reactivity 1renal artery response to ␤-adrenergic stimuli and sensitivity to adenylyl cyclase in growth-restricted rats 184,186,187 Altered vascular reactivity 2flow-mediated dilation in LBW children 107,[188][189][190] 1uric acid Endothelial dysfunction Impaired vascular structure and capillary density Altered RAS Administration of inhibitors of RAS abrogates later hypertension 4,30,111,177,191 Administration of angiotensin II causes increased hypertensive response Evidence of expression of AT1R and AT2R and ACE activity are divergent at different stages and in different models of programming Overall, programmed suppression of intrarenal RAS during nephrogenesis and postnatal upregulation of AT1R are most consistent Altered sodium handling 2fractional excretion of sodium 22,109,110,174,192 1expression of BSC1 and TSC 1expression of glucocorticoid receptor 1expression of glucocorticoid responsive ␣1 and ␤1 subunits of Na/K-ATPase 1expression of NHE3 1expression of ␤ and ␥ ENaC Increased sympathetic nervous system activity Renal denervation reduced systolic BP and sodium transporter expression 193 Catch-up growth/obesity Higher BP in children who catch up fastest 98,154 Reduced flow-mediated dilation with higher rate of weight gain AT1R, angiotensin subtype 1 receptor; AT2R, angiotensin subtype 2 receptor; BSC1, bumetanide-sensitive co-transporter; ENaC, epithelial sodium channel; NHE3, sodium hydrogen exchanger; RAS, renin-angiotensin system; TSC, thiazide-sensitive co-transporter.…”

Reactive oxygen species and vascular biology: implications in human hypertension

“…134,135 OXIDATIVE STRESS AND HUMAN HYPERTENSION Almost all experimental models of hypertension show some form of oxidative excess including genetic forms (spontaneously hypertensive rats, stroke-prone spontaneously hypertensive rats), surgically induced (2K1C, aortic banding), endocrine-induced (Ang II, aldosterone, deoxycorticosterone acetate) and diet-induced hypertension (salt, fat). [21][22][23][136][137][138] Sources of ROS in experimental models include Noxes (Nox1, Nox2 and Nox4), xanthine oxidase, uncoupled nitric oxide synthase and mitochondrial oxidases. Mice deficient in ROSgenerating enzymes have lower blood pressure compared with wild-type counterparts, and Ang II infusion fails to induce hypertension in these mice.…”

Reactive Oxygen Species, Vascular Noxs, and Hypertension: Focus on Translational and Clinical Research

“…In addition, recent evidence indicates that the immune system may be involved. Oxidative stress precedes the development of hypertension in experimental models, and it may play a role in fetal programming and the development of hypertension in adult life (153). This may be related to alterations in antioxidant status, as impaired renal catalase and glutathione peroxide mRNA expression and activity were found to precede the development of hypertension in SHR (198).…”