Epidemiological [46,87,121,122] and experimental [6,14,97] data also suggest that obesity-related microvascular dysfunction may contribute to the development of cardiometabolic risk factors such as hypertension and insulin resistance. In most forms of experimental and clinical hypertension, peripheral vascular resistance is increased in proportion to the increase in blood pressure [69]. This increase in peripheral vascular resistance is likely to reflect Temsirolimus datasheet changes in the microcirculation. In several tissues, both microvascular endothelium-dependent vasodilatation and capillary density has been found to correlate inversely with blood pressure in hypertensive and normotensive

subjects

[22,98–100]. Although it has been known for many years that increased wall-to-lumen ratio and microvascular rarefaction can be secondary to sustained elevation X-396 purchase of blood pressure [69], there is also evidence that abnormalities in the microcirculation precede and thus may be a causal component of high blood pressure. Microvascular rarefaction, similar in magnitude to the rarefaction observed in patients with established hypertension, can already be demonstrated in subjects with mild intermittent hypertension and in normotensive subjects with a genetic predisposition to high blood pressure [3,88]. Moreover, in hypertensive subjects, capillary rarefaction in muscle has been shown to predict the increase in mean arterial pressure over two decades [39]. More recently, a smaller retinal arteriolar diameter has been shown to predict the occurrence and development of hypertension in a prospective, population-based study of normotensive middle-aged persons [46,121]. Other, indirect, Tau-protein kinase evidence comes from studies demonstrating that inhibitors of angiogenesis and especially inhibitors of VEGF/VEGFR-2 signaling cause arterial hypertension, which, in severity,

is paralleled by microvascular rarefaction, and reversible upon discontinuation of the angiogenesis inhibitor [18,70]. In addition, calculations by mathematical modeling of in vivo microvascular networks predict an exponential relationship between capillary and arteriolar number and vascular resistance [18,34]. Total vessel rarefaction up to 42% (within the range observed in hypertensive humans) can increase tissue vascular resistance by 21% [43]. In a microvascular network maturation model, rarefaction of vessels below a critical diameter was shown to be important in determining the mature network structure and its response to hypertension [47]. It was shown that there was a network density threshold below which resistance to flow dramatically increased. In addition, simulating hypertension in a mature and already compromised network leads to further rarefaction [48].