**6. Vascular endothelium**

In addition to the essential VSM and autonomic neural mechanisms, a functional endothelium is equally important for appropriate blood flow control and modulation. VEC dysfunction is increasingly accepted as a common trait of nearly all forms of CVD and is often the initial insult in CVD pathogenesis. Though environmental and genetic factors consistently contribute to these disease states as well, the onset of vascular endothelial dysfunction can also be caused by smoking, hypertension, and/or diabetes [1]. Contrary to this evidence, Horvath and colleagues argue that arterial stiffness is not directly related to a properly functioning endo‐ thelium [9]. This is true in the sense that the mechanical elasticity of the vessel may compress or expand due to pressure changes alone, but a functional endothelium is nonetheless important for its contribution to baroreceptor function and is often a target for CVD prevention. It is well described that reduced NO bioavailability within the vasculature has a direct influence on VEC dysfunction [5]. Nonetheless, in the absence of an intact or functional endothelium, the VSM layer is still capable of receiving NO from alternate NOS isoforms independent of the endothelial layer. For example, inducible nitric oxide synthase (iNOS) either from circulating cells or platelets or from local adventitial nerves can provide VSM with bioavailable NO independent of endothelial contribution. Also, since iNOS is located within VSM it can intrinsically synthesize NO, in turn facilitating vasorelaxation in autocrine fashion. It should be noted though that the canonical pathway of vasodilation begins with VEC activation as described.

In sum, hemodynamics and intrinsic and extrinsic neural control of blood flow including sensory input to the carotid sinus and the ensuing baroreflex pathway are essential, yet can become compromised under many disease states. The causes of this dysfunction are not entirely understood, but research suggests that there is a direct link between autonomic output and neural integrity and vascular function/dysfunction and the establishment and/or mainte‐ nance of CVD. Thus, the preservation of the baroreceptor reflex within the carotid sinus as well as intrinsic/extrinsic neural control mechanisms are essential for ensuring adequate arterial blood supply to the brain in CVD prophylaxis.
