Local regulation of microvascular blood flow is a complex process in which the needs of the tissue must be communicated to the vasculature, enabling the appropriate matching of O2 supply to demand. We hypothesize that the red blood cell is not only the major O2 carrier but also serves as an O2 sensor and affecter of changes in O2 delivery via its release of ATP, which subsequently binds to P2y receptors on the vascular endothelium, altering vessel caliber. Using the hamster as a model, we determined that the efflux of ATP from red blood cells after exposure to low-PO2 (PO2 = 17 +/- 6 mmHg) and low-pH (pH = 7.06 +/- 0.07) solutions was significantly (P < 0.01) greater than that after exposure to normoxic, normal pH (PO2 = 87 +/- 4; pH = 7.38 +/- 0.04) solutions, indicating that two factors that are associated with an impaired O2 supply relative to demand increase the release of ATP from the red blood cell. To ascertain whether ATP alters vascular caliber, we applied 10(-6) M ATP intraluminally to arterioles of the retractor muscle, using a micropressure system. Vessel diameter increased 8 and 10%, 140 +/- 60 microns upstream of the site of infusion after 50- and 500-ms pulses, respectively. Application of ATP to arteriolar and venular capillaries induced a 31 and 81% increase in red blood cell supply rate, respectively. These results support our hypothesis that the red blood cell is more than just an O2 carrier and has a direct role in the regulation of vascular tone.

Through oxygen-dependent release of the vasodilator ATP, the mobile erythrocyte plays a fundamental role in matching microvascular oxygen supply with local tissue oxygen demand. Signal transduction within the erythrocyte and microvessels as well as feedback mechanisms controlling ATP release have been described. Our understanding of the impact of this novel control mechanism will rely on the integration of in vivo experiments and computational models.1548-9213/09 8.00

The matching of blood flow with metabolic need requires a mechanism for sensing the needs of the tissue and communicating that need to the arterioles, the ultimate controllers of tissue perfusion. Despite significant strides in our understanding of blood flow regulation, the identity of the O(2) sensor has remained elusive. Recently, the red blood cell, the Hb-containing O(2) carrier, has been implicated as a potential O(2) sensor and contributor to this vascular control by virtue of its concomitant carriage of millimolar amounts of ATP, which it is able to release when exposed to a low-O(2) environment. To evaluate this possibility, we exposed perfused cerebral arterioles to low extraluminal O(2) in the absence and presence of red blood cells or 6% dextran and determined both vessel diameter and ATP in the vessel effluent. Only when the vessels were perfused with red blood cells did the vessels dilate in response to low extraluminal O(2). In addition, this response was accompanied by a significant increase in vessel effluent ATP. These findings support the hypothesis that the red blood cell itself serves a role in determining O(2) supply to tissue.

The contributing effect of cerebrovascular pathology in Alzheimer's disease (AD) has become increasingly appreciated. Recent evidence suggests that amyloid-␤ peptide (A␤), the same peptide found in neuritic plaques of AD, may play a role via its vasoactive properties. Several studies have examined young Tg2576 mice expressing mutant amyloid precursor protein (APP) and having elevated levels of soluble A␤ but no cerebral amyloid angiopathy (CAA). These studies suggest but do not prove that soluble A␤ can significantly impair the cerebral circulation. Other studies examining older Tg2576 mice having extensive CAA found even greater cerebrovascular dysfunction, suggesting that CAA is likely to further impair vascular function. Herein, we examined vasodilatory responses in young and older Tg2576 mice to further assess the roles of soluble and insoluble A␤ on vessel function. We found that (1) vascular impairment was present in both young and older Tg2576 mice; (2) a strong correlation between CAA severity and vessel reactivity exists; (3) a surprisingly small amount of CAA led to marked reduction or complete loss of vessel function; 4) CAA-induced vasomotor impairment resulted from dysfunction rather than loss or disruption of vascular smooth muscle cells; and 5) acute depletion of A␤ improved vessel function in young and to a lesser degree older Tg2576 mice. These results strongly suggest that both soluble and insoluble A␤ cause cerebrovascular dysfunction, that mechanisms other than A␤-induced alteration in vessel integrity are responsible, and that anti-A␤ therapy may have beneficial vascular effects in addition to positive effects on parenchymal amyloid.

The mechanisms responsible for subarachnoid hemorrhage (SAH)-induced vasospasm are under intense investigation but remain incompletely understood. A consequence of SAH-induced vasospasm, cerebral infarction, produces a nonrecoverable ischemic tissue core surrounded by a potentially amenable penumbra. However, successful treatment has been inconsistent. In this review, we summarize the basic molecular biology of cerebrovascular regulation, describe recent developments in molecular biology to elucidate the mechanisms of SAH-induced vasospasm, and discuss the potential contribution of cerebral microcirculation regulation to the control of ischemia. Our understanding of the pathogenesis of SAH-induced vasospasm remains a major scientific challenge; however, molecular biological techniques are beginning to uncover the intracellular mechanisms involved in vascular regulation and its failure. Recent findings of microvascular regulatory mechanisms and their failure after SAH suggest a role in the development and size of the ischemia. Progress is being made in identifying the various components in the blood that cause SAH-induced vasospasm. Thus, our evolving understanding of the underlying molecular mechanism may provide the basis for improved treatment after SAH-induced vasospasm, especially at the level of the microcirculation.